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Aetna Aetna
Clinical Policy Bulletin:
Cervical Cancer Screening and Diagnosis
Number: 0443
(Replaces CPB 359)

Policy

  1. Consistent with guidelines from the U.S. Preventive Services Task Force and the American College of Obstetricians and Gynecologists, Aetna considers annual cervical cancer screening with conventional or liquid-based Papanicolaou (Pap) smears a medically necessary preventive service for nonhysterectomized women age 21 years and older.

  2. Aetna considers Pap screening medically necessary beginning in adolescense in HIV-infected women. The ACOG guidelines on cervical cancer in adolescents (2010) recommend that adolescents with HIV have cervical cytology screening twice in the first year after diagnosis and annually thereafter.

  3. Aetna considers Pap screening medically necessary in sexually active immunocompromised adolescent women, including those who have received an organ transplant or those with long-term steroid use. According to ACOG guidelines (2010), sexually active immunocompromised adolescents, including those who have received an organ transplant or those with long-term steroid use, should undergo screening after the onset of sexual activity and not wait until 21 years of age.  The testing should be done at 6-month intervals during the first year of testing and then annually thereafter.

  4. Aetna considers Pap screening medically necessary beginning in adolescence in women diagnosed with cervical dysplasia or cervical cancer, with testing twice in the first year after diagnosis and annually thereafter.

  5. Aetna considers Pap smears medically necessary beginning in adolescence in sexually active women who have been exposed in utero to diethylstilbestrol (DES). Testing should begin after the onset of sexual activity, and should be done at 6-month intervals during the first year of testing and then annually thereafter.

  6. Pap smears are considered experimental and investigational for all other women under 21 years of age because they have no proven value for these younger women.

  7. Aetna considers Pap smear screening not medically necessary for women who have undergone complete (total) hysterectomy for benign disease (e.g., no evidence of cervical neoplasia or cancer) or have absent cervix.

    Note: Medically necessary cervical cancer screening is covered under plans that cover routine physical exams, routine gynecological exams and/or routine Pap smears.  Please check benefit plan descriptions for details.

  8. Aetna considers diagnostic Pap smears medically necessary when any of the following conditions is met:

    1. Pap smear is accompanied by a diagnosis of a malignancy of the female genital tract (i.e., cervix, ovary, uterus, or vagina); or
    2. There is a description of symptoms or a disease requiring diagnosis by a Pap smear, for example:

      1. Abnormal vaginal bleeding or discharge
      2. Chronic cervicitis
      3. Vaginal tumor; or

    3. Following gynecological surgery for cancer; or
    4. Member has been exposed to diethylstilbestrol (DES); or
    5. Member has any of the following risk factors for cervical cancer:

      1. History of cervical, vaginal or vulvar cancer
      2. HIV infection
      3. History of genital HPV infection
      4. Immunosuppression
      5. Multiple sexual partners
      6. Previously abnormal Pap smear
      7. Previous sexually transmitted disease.

    Aetna considers diagnostic Pap smears experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.

  9. Aetna considers automated liquid-based thin-layer slide preparation methods (e.g., ThinPrep® PapTestTM, SurePrepTM Liquid Based Pap Test, AutoCyte PREP SystemTM ) medically necessary as an alternative to conventional Pap smears when the criteria for conventional Pap smears are met.

  10. Aetna considers automated cervical cancer slide interpretation systems (e.g., FocalPoint Slide Profiler (formerly AutoPap), PAPNET) a medically necessary adjunct to cervical cancer screening.

  11. Aetna considers testing for high-risk strains of human papilloma virus (HPV) DNA using Food and Drug Administration (FDA)-approved techniques (e.g., Hybrid Capture II, cobas HPV PCR) medically necessary for adult women 21 years of age or older with any of the following indications:

    1. Assessment of women with atypical squamous cells of undetermined significance (ASCUS).  This is consistent with the National Cancer Institute's interim guidelines for managing abnormal cervical cytology as well as the position of the American Society for Colposcopy and Cervical Pathology (ASCCP) for the management of ASCUS.
    2. Follow-up of women with ASCUS who have a previously positive HPV DNA test and negative colposcopy results within the past 2 years.
    3. Follow-up of women with low-grade squamous intra-epithelial lesions (LSIL) who have had negative colposcopy results within the past 2 years.
    4. Follow-up of women with atypical squamous cells: Cannot exclude high-grade SIL (ASC-H) who have negative colposcopy results within the past 2 years.
    5. Use in combination with Pap smears for screening women aged 30 years and older.  If this combination is used for screening, it is not considered medically necessary to re-screen women who receive negative results on both tests more frequently than every 3 years.  This policy is consistent with guidelines from the American College of Obstetricians and Gynecologists (2009).
    6. Assessment of women with atypical glandular cells not otherwise specified (AGC NOS).
    7. Follow-up of women with AGC NOS who have had negative colposcopy results within the past 2 years.
    Note: The medically necessary indications for HPV DNA testing are not affected by pregnancy status.
  12. Aetna considers HPV testing experimental and investigational for the following indications:

    1. Use as a primary screening test for cervical cancer in women younger than 30 years of age.  According to evidence-based guidelines from the U.S. Preventive Services Task Force (2003), the medical literature does not support HPV testing as a screening test for cervical cancer for younger individuals whose cervical cytology is normal or is unknown.
    2. For selecting candidates for cervical cancer vaccine.  The Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices does not recommend HPV testing to select persons for cervical cancer vaccine. 
    3. For testing members with definitively positive cervical cytology, other than follow-up of women with ASC-H, LSIL or AGC NOS and negative colposcopy.
    4. Testing for low-risk HPV strains.
    5. Testing of men.
    6. Use for indications other than detection of cervical cancer, such as testing for infection following exposure to HPV.
    7. For use in girls and women less than 21 years of age.
    8. Use for all indications other than those listed in section V above.

  13. Aetna considers cervicography or speculoscopy (Pap-Sure) experimental and investigational for the screening or diagnosis of cervical cancer because of a lack of adequate clinical studies related to their use for these indications.

  14. Aetna considers video colpography experimental and investigational for cervical cancer screening or diagnosis because of a lack of adequate evidence of its effectiveness for these indications.

  15. Aetna considers optical detection systems (e.g., the Luma cervical imaging system) experimental and investigational for cervical cancer screening or diagnosis because of insufficient evidence of their effectiveness for these indications.

  16. Aetna considers the ResolveTM laboratory testing kit (GynecorTM, Glen Allen, VA) experimental and investigational for cervical cancer screening or diagnosis because of insufficient evidence of its effectiveness for these indications.

  17. Aetna considers the use of methylation markers for cervical cancer screening experimental and investigational because of insufficient evidence of their effectiveness.

See also CPB 0650 - Polymerase Chain Reaction Testing: Selected Indications.



Background

Pap smears consist of cells removed from the cervix, which are specially prepared for microscopic examination.  The cells are removed by brushing or scraping the cervix during a pelvic examination and then placing the cells on one or more glass slides.  Each slide typically contains hundreds of thousands of cells.  All Pap smears should be sent to an accredited laboratory to be stained, examined under a microscope, and interpreted.  The test is used as the principal screening test to detect cervical cancer in asymptomatic women.  It can detect precancerous changes or cancer of the cervix or vagina.  A Pap test will only rarely detect cancer of the ovaries or endometrial cancer.  It can also find some infections of the cervix and vagina.

The American Academy of Family Physicians recommends that all women who are or have been sexually active, or who have reached age 18, should have annual Pap smears.  The American Cancer Society, National Cancer Institute, and American Medical Association recommend that cervical cytology screening should begin within 3 years of onset of sexual activity or age 21.  The recommendation allows less frequent Pap testing after 3 or more annual smears have been normal, at the discretion of the physician.  For women who have had repeated negative tests, the marginal gain from screening more often than every 3 years decreases sharply.  However, because of the difficulty in identifying patients at increased risk for cervical cancer, most physicians will recommend a Pap test be performed at least once-yearly.

The American College of Obstetricians and Gynecologists (ACOG, 2009) recommend that cervical cytology screening begin at age 21 regardless of age at onset of sexual activity and from age 21 to 29, testing is recommended every 2 years but should be more frequent in women who are HIV-positive, immunosuppressed, were exposed in- utero to diethylstilbestrol (DES), or have been treated for cervical intraepithelial neoplasia (CIN) grade 2, 3 or cervical cancer.  The ACOG guidelines on cervical cancer in adolescents (2010) recommend that adolescents with HIV have cervical cytology screening twice in the first year after diagnosis and annually thereafter.  Sexually active immunocompromised adolescents, including those who have received an organ transplant or those with long-term steroid use, should undergo screening after the onset of sexual activity and not wait until 21 years of age.  The testing should be done at 6-month intervals during the first year of testing and then annually thereafter.  Beginning at age 30, women who have 3 consecutive negative screens and who do not fit the criteria above for more frequent screening, may be tested every 3 years.  Co-testing with cervical cytology and high-risk HPV typing is also appropriate and if both tests are negative, re-screening in 3 years is recommended.

After age 65, there is no clear consensus on the need for Pap smears in women who have had previous adequate screening.  The American Academy of Family Physicians recommends that at age 65, screening may be discontinued if there is documented evidence of previously negative smears; however, these recommendations are currently under review.  The ACOG (2009) recommend discontinuation of screening after age 65 or 70 in women with 3 or more negative consecutive tests and no cervical abnormalities during the previous 10 years.  Women with histories of CIN grade 2, 3 or cancer should undergo annual screening for 20 years after treatment.  The American College of Physicians (ACP) recommends Pap smears every 3 years for women aged 20 to 65, and every 2 years for women at high-risk.  The ACP also recommends screening women aged 66 to 75 every 3 years if not screened in the 10 years before age 66.

Pap testing need not be performed for women who had a hysterectomy for benign disease; however, women who had a hysterectomy performed in which the cervix was left intact probably still require screening.  However, a recent study by Sirovich and Welch (2004) indicated that many U.S. women who have undergone hysterectomy are undergoing Pap smear screening despite the U.S. Preventive Services Task Force's recommendation that Pap smear screening is unnecessary for women who have undergone a complete hysterectomy for benign disease.

A federally funded survery of 1,100 clinicians (internists, family practitioners, or obstetrician-gynecologists) found that only about 1/5 consistently follow guidelines for Pap testing (Yabroff et al, 2009).  While over 80 % said that at least one set of screening guidelines (e.g., U.S. Preventive Services Task Force) was "very influential" in their practices, only 22 % recommended guideline-consistent care for every clinical scenario included in the survey.  Obstetrician-gynecologists were less guideline-concordant than the other specialties.  Of note, 1/3 of participants recommended annual Pap testing for an 18-year old who hadn't had sexual intercourse, while almost 1/2 continued to recommend Pap testing for a women whose cervix had been removed for benign reasons.

Repeat Pap smears may be indicated 3 to 4 months following local treatment of vaginal infection/inflammation, and 2 to 3 months following a Pap test suggestive of mild dyskaryosis or if the initial Pap smear results were unsatisfactory due to inadequate sampling.

A standardized method of reporting cytology findings was developed by the National Cancer Institute called the "Bethesda System".  In the Bethesda System, atypical squamous cells fall into 2 categories: (i) atypical squamous cells of undetermined significance (ASCUS) and (ii) atypical squamous cells: cannot exclude HSIL (ASC-H).  Cervical cancer precursors fall into 2 categories: (i) low-grade squamous intraepithelial lesions (LSIL) and (ii) high-grade squamous intraepithelial lesions (HSIL).  Low-grade squamous intraepithelial lesions include CIN 1 (mild dysplasia) and the changes of HPV, termed koilocytotic atypia.  High-grade squamous intraepithelial lesions include CIN 2 and CIN 3 (moderate dysplasia, severe dysplasia, and carcinoma in situ ).  Other classification systems in use include the Dysplasia/CIN System and the Papanicolaou System.

Currently there are no formal guidelines for anal Pap smear screening.  The most recent recommendations from the Centers for Disease Control and Prevention (Workowski and Berman, 2006) stated: "Routine testing for anal cytologic abnormalities or anal HPV infection is not recommended until more data are available on the reliability of screening methods, the safety of and response to treatment, and programmatic considerations."

Automated Liquid-Based Thin-Layer Slide Preparation (e.g., ThinPrep, SurePath, AutoCyte PREP)

To decrease the number of false-negative Pap smears, new technologies for preparing the Pap smear have been approved by the U.S. Food and Drug Administration (FDA).

The ThinPrep® PapTestTM  (Cytyc Corp., Marlborough, MA), and SurePath (TriPath Imaging Inc., Burlington, NC) are automated liquid-based thin layer slide preparation techniques.  With the ThinPrep System, a conventional Pap smear is not performed.  Using a spatula and a brush or a cervical broom, the cervical area is sampled and the devices are rinsed in a fixative solution.  The slide is then automatically made in the laboratory, which decreases the possibility of air-drying artifacts.  It is then stained and read by a technician or a cytopathologist.  SurePath (formerly known as AutoCyte PREP) is another liquid-based thin-layer sample preparation system that uses centrifugation to separate cells from obscuring material, and automatically prepares and stains cytology slides.

An assessment of liquid-based cervical cytology systems by the Institute for Clinical Systems Improvement (ICSI, 2003) concluded that liquid-based cytology is an acceptable alternative to conventional Pap testing for cervical cancer screening.  The ICSI technology assessment made the following findings:

  • For the detection of pre-invasive cervical lesions, liquid-based cytology is comparable to conventional Pap; there is no evidence of a change in the rate of cancer detection when liquid-based samples are analyzed.
  • For minor grade lesions, there is evidence of a higher detection rate with liquid-based cytology.  As a result, liquid-based cytology acts to normalize the rate of detection of atypical squamous cells of undetermined significance (ASCUS) so that pathologists can reach the 3 % to 5 % ASCUS rate expected (Bethesda criteria).  More accurate detection of ASCUS helps to better identify patients who need further testing.  Inter-observer validity is higher with LBC.
  • Of 11 studies cited in the ICSI technology assessment that presented test results as either satisfactory, satisfactory but limited by, or unsatisfactory, 8 found a higher rate of satisfactory samples with liquid-based cytology.  Between 75.6 % and 97.7 % of liquid-based cytology preparations were satisfactory compared with 60.5 % to 97.5 % with conventional Pap preparations.
  • The ICSI report cited the results of a meta-analysis of 15 studies that reported a sensitivity of 80 % for liquid-based cytology and 72 % for conventional Pap testing predominantly for the detection of low-grade squamous intraepithelial lesions or more severe (LSIL+) by histology and/or independent pathology review of slides with a Pap test result of LSIL+.  Specificity did not differ between conventional and liquid-based cytology preparations.

A technology assessment by the Canadian Coordinating Office for Health Technology Assessment found that "[e]vidence (based primarily on results from split-sample trials) suggests that compared with Pap smears, the use of [liquid-based cytology] reduces the proportion of unsatisfactory specimens and generates fewer false negatives for ordinary populations, but not for high-risk populations" (Noorani et al, 2003).

In its updated guidelines on cervical cancer screening, the American Cancer Society has stated that liquid-based thin-layer Pap smears are an acceptable alternative to conventional Pap smears (Saslow et al, 2002).  "As an alternative to conventional cervical cytology smears, cervical screening may be performed every two years using liquid-based cytology; at or after age 30, women who have had 3 consecutive, technically satisfactory normal/negative cytology results may be screened every 2 to 3 years (unless they have a history of in utero DES exposure, are HIV+, or are immunocompromised)."

An assessment by the Danish Centre for Evaluation and Health Technology Assessment (DACEHTA, 2005) concluded that "no scientific basis has been found to suggest any difference in clinical or health economic effect between liquid based cytology (LBC) and conventional Pap smear (CPS)."  The report noted that "[i] the objective is to improve the clinical or health economic effectiveness, the report demonstrates that an increased coverage rate and an expansion of the age interval included in screening programmes for cancer of the uterine cervix from 59 to 69 years of age would be the more efficient strategy."

A recent large-scale clinical trial found that liquid-based cytology does not perform better than conventional Pap tests in terms of relative sensitivity and PPV for detection of cervical cancer precursors.  In a randomized double-blind controlled trial, Siebers and colleagues (2009) compared liquid-based cytology with conventional cytology for detection of cervical cancer precursors in women (n = 89,784) aged 30 to 60 years participating in the Dutch cervical screening program.  A total fo 122 practices were assigned to use liquid-based cytology and screened 49,222 patients and 124 practices were assigned to use the conventional Pap test and screened 40,562 patients.  Patients were followed for 18 months.  The adjusted detection rate ratios for CIN grade 1+ was 1.01 (95 % confidence interval [CI]: 0.85 to 1.19); for CIN grade 2+, 1.00 (95 % CI: 0.84 to 1.20); for CIN grade 3+, 1.05 (95 % CI: 0.86 to 1.29); and for carcinoma, 1.69 (95 % CI: 0.96 to 2.99).  The adjusted positive predictive value (PPV) ratios, considered at several cytological cut-offs and for various outcomes of CIN did not differ significantly from unity. 

Automated System (FocalPoint, PAPNET)

Automated slide analysis devices (e.g., PapNet (Neuromedical Systems Inc.), FocalPoint (formerly AutoPap) (TriPath Technologies, Inc., AutoCyte SCREEN (AutoCyte, Inc.)) are designed to partially automate screening of Pap smears.  The primary focus of current research is on use of image analysis as a primary screening device, where Pap smear slides are translated into digitalized images for automated image analysis.  Slides that are identified by automated image analysis as possibly abnormal are passed on for manual interpretation.  Slides that are identified by automated image analysis as very unlikely to contain abnormal cells may not be examined manually, or a random sample may be spot checked manually.  Automated slide analysis devices may also be used to rescreen slides that are reported as negative or inadequate.

Although it is not known whether programs employing automated slide analysis are more effective than manual screening in detecting more cervical cancers, automated slide analysis devices have become standard of care.  An Agency for Healthcare Research and Quality technology assessment of cervical cancer screening techniques (McCrory et al, 1999) concluded that there is substantial uncertainty about the estimates of sensitivity and specificity of cervical cancer screening using automated slide analysis devices compared with conventional manual screening, which in turn results in substantial uncertainty about the estimates of the effectiveness and cost-effectiveness of these techniques.  "Although it is clear that both thin-layer cytology and computerized rescreening technologies provide an improvement in effectiveness at higher cost, the imprecision in estimates of effectiveness makes drawing conclusions about the relative cost-effectiveness of thin-layer cytology and computerized rescreening technologies problematic."

A technology assessment for the Minnesota Health Technology Advisory Committee (1999) concluded: "Studies of these methods demonstrate that computer-assisted cervical cancer screening and rescreening modestly improves detection of false-negative smears as compared with conventional manual screening.  The majority of false-negative smears detected are low-grade squamous intraepithelial lesions (LGSIL), reactive or reparative changes, or atypical squamous cells of undetermined significance (ASCUS) rather than the more serious premalignant or malignant lesions.  Some studies have shown that computer-assisted Pap smear screening may marginally improve health outcome for some patients.  The net health benefits of computer-assisted screening have not been proven.  Studies examining the cost-effectiveness of the new technologies indicate that the cost-benefit of computer-assisted rescreening technologies is less favorable than any manual rescreening alternatives."

An assessment of the use of automated slide analysis devices in cervical cancer screening conducted by the Research Triangle Institute Evidence-Based Practice Center for the Agency for Healthcare Research and Quality (Hartmann et al, 2002) concluded that "[o]verall, the quality of this literature is poor for the purposes of making decisions about choice of screening systems in US populations.  No randomized trials or prospective cohort studies relate use of a screening modality over time to outcomes for individual women.  The cost-effectiveness of use of new technologies has only been estimated, not measured directly."

More recently, the U.S. Preventive Services Task Force (USPSTF, 2003) reached the following conclusions regarding cervical cancer screening using automated slide analysis devices: "The USPSTF concludes that the evidence is insufficient to recommend for or against the routine use of new technologies to screen for cervical cancer.  The USPSTF found poor evidence to determine whether new technologies, such as liquid-based cytology, computerized rescreening, and algorithm based screening, are more effective than conventional Pap smear screening in reducing incidence of or mortality from invasive cervical cancer.  Evidence to determine both sensitivity and specificity of new screening technologies is limited.  As a result, the USPSTF concludes that it cannot determine whether the potential benefits of new screening devices relative to conventional Pap tests are sufficient to justify a possible increase in potential harms or costs.

An assessment for the European Cervical Cancer Screening Network's Guidelines for Quality Assurance in Cervical Cancer Screening (Nieminen, 2003) summarized the current evidence for automated cervical cancer slide analysis devices: "There are several articles published concerning the performance of automation assisted screening.  They show generally a better sensitivity with at least same specificity than conventional screening.  Most of these articles have been retrospective (quality control) and/or relatively small numbers of smears have been studied.  However, randomized, prospective public health trials in primary screening setting have been published very few.  The show equal or slightly better performance compared to manual conventional screening …. When implementing the new methods, it is needed to carefully ascertain and evaluate the performance of the method in primary (public health) screening up to the final invasive end points with randomized prospective studies."

An assessment for the National Coordinating Centre for Health Technology Assessment (Willis et al, 2005) concluded: "As in previous health technology assessments on this subject, the conclusion is that the available evidence on test performance, impact on process and cost-effectiveness is still insufficient to recommend implementation of automated image analysis systems.  The priority for action remains further research."

Wain (1997) has commented that "[t]he performance of automated techniques in quality assurance should be assessed against other methods of quality assurance, such as random re-screening of a mandated proportion of smears, directed re-screening of 'high-risk' groups and 'rapid re-screening'."

In its updated guidelines on cervical cancer screening, the American Cancer Society expert review panel (Saslow et al, 2002) only considered screening technologies with sufficient published clinical data, and excluded cervical cancer screening with automated slide analysis devices from its consideration.

HPV Testing

Human papillomavirus (HPV) has been associated with the development of CIN and invasive cancer of the cervix.  Recent prospective studies have shown that abnormal Pap smears that are positive for oncogenic HPV strains are much more likely to be associated with abnormal colposcopic findings than abnormal Pap smears that are HPV negative.  There is no proven value for testing for additional "low-risk" strains of HPV that have not been associated with substantially elevated cancer risk.

HPV testing has been used as an adjunctive reflex test in women with ASCUS to identify those at highest risk for cervical cancer, who should go on to receive definitive colposcopy.  HPV testing of patients with ASCUS can be used to identify patients at highest risk of underlying cervical dysplasia, and minimize the number of unnecessary colposcopic examinations in women who have no disease.  Women with ASCUS who have a positive HPV and no lesions on colposcopy should be followed-up with repeat Pap testing at 6 and 12 months or with HPV testing at 12 months.  Current guidelines do not recommend reflex testing of women with squamous intraepithelial lesions (HSIL, ASC-H, or LSIL).  However, guidelines from the American Society of Colposcopy and Cervical Cytology (Wright et al, 2002; Wright et al, 2007) recommend that women with LSIL or ASC-H with no lesions on colposcopy should be followed-up with repeat Pap testing at 6 and 12 months or with HPV testing at 12 months. 

HPV testing has also been proposed as a primary screening test to be performed simultaneously with Pap smear screening.  Digene Corp. received FDA approval for a test that combines the Pap smear with a genetic exam for 13 oncogenic strains of HPV.  Aetna, however, does not cover HPV testing as a screening test for cervical cancer for women less than 30 years of age because the evidence is insufficient to determine whether HPV screening reduces the incidence of or mortality from invasive cervical cancer.  Aetna's policy is consistent with updated recommendations of the U.S. Preventive Services Task Force (USPSTF) (2003).  The USPSTF concluded that the evidence is insufficient to recommend for or against the routine use of human papillomavirus (HPV) testing as a primary screening test for cervical cancer.  The USPSTF found "poor evidence to determine the benefits and potential harms of HPV screening as an adjunct or alternative to regular Pap smear screening."

The ACOG (2009) concluded, based on "good and consistent scientific evidence" that the use of a combination of cervical cytology and HPV DNA screening is appropriate for women aged 30 years and older.  According to ACOG (2009), if this combination is used, women who receive negative results on both tests should be re-screened no more frequently than every 3 years.  ACOG's recommendation was based on the results of studies that demonstrated that women aged 30 years and older who had both negative cervical cytology test results and negative high-risk type HPV-DNA test results were at extremely low-risk of developing CIN 2 or CIN 3 during the next 4 to 6 years.  ACOG guidelines explain that any woman aged 30 years or older who receives negative test results on both cervical cytology screening and HPV DNA testing should be re-screened no more frequently than every 3 years.  The ACOG guidelines state that the combined use of these modalities has been shown to increase sensitivity but also decrease specificity and increase cost.  However, ACOG estimated that the increase in screening interval will offset the cost of this new screening regimen.

The ACOG guidelines (2009) stated that the combination of cytology and HPV DNA screening should be restricted to women aged 30 years and older because transient HPV infections are common in women younger than 30 years, and a positive test result may lead to unnecessary additional evaluation and treatment.  The ACOG guidelines on cervical cancer in adolescents (2010) stated that HPV testing is not recommended at any time in adolescents because of the high prevalence of HPV infection in adolescents and there is little utility in HPV testing in this population; there are no clinical situations, screening, triage, or follow-up that require HPV testing in this population and if conducted, a positive test result should not influence management.  The guidelines stated that there is no role for HPV testing in the patient before HPV vaccination.  Furthermore, the ACOG guidelines (2010) stated that adolescents who have low- to high-grade precancerous lesions (dysplasia) -- with the exception of cervical intraepithelial neoplasia 3 (CIN 3) -- generally should be managed by periodic observation.  The guidelines stated that re-screening can be delayed until age 21 when the Pap test results show regression of the dysplasia, but annual screening also is an acceptable alternative.

Published studies of cervical cancer screening using a combination of cytology and HPV DNA tests have predominantly employed conventional Pap smears for assessment of cervical cytology.  Although there are no studies directly comparing the screening performance of HPV-cytology combination testing using a conventional Pap versus liquid-based cervical cytology, available indirect evidence suggests that there is no clinically significant difference in the screening performance of HPV-cytology combination testing regardless of whether conventional or liquid-based cervical cytology is used (Lorincz and Richart, 2003).

The National Cancer Institute is currently sponsoring a multi-center 5-year clinical trial directed at determining the role of HPV testing in the management of cervical disease.  Interim guidelines for the management of abnormal cytologic findings in the cervix were developed at a work-shop sponsored by the NCI, which concluded that HPV testing can be used as an adjunctive test to help identify patients at low- or high-risk of developing CIN and cancer.  The American Society of Colposcopy and Cervical Pathology has also issued guidelines for the management of ASCUS which incorporated HPV testing and typing to determine which women with ASCUS should undergo colposcopy.

There are no current guidelines recommending HPV testing of men (CDC, 2006; Workowski and Berman, 2006).  There is no FDA-approved HPV test for men, and there are no studies demonstrating benefit of testing men for HPV infection.  Unlike with cervical ASCUS, HPV typing has not been shown to aid in predicting which patients with anal ASCUS are at risk for high-grade anal intraepithelial neoplasia (AIN) (Panther et al, 2003).

Saqi and colleagues (2006) evaluated the potential role of HPV DNA testing on atypical glandular cells (AGC) cases.  Hybrid Capture 2 (Digene Corp.) testing was performed on 144 cervical/endo-cervical AGC specimens.  A total of 103 of 144 cases had follow-up; 60/103 (58.3 %) were high-risk HPV negative and 43/103 (42.3 %) were high-risk HPV positive.  Of 43 HPV-positive patients, 37 had adenocarcinoma in situ (AIS), ASCUS, or cervical squamous intra-epithelial neoplasia, while only 1 patient without high-risk HPV had a squamous intraepithelial neoplasia.  Furthermore, most high-risk HPV positive AGC cases harbored high-grade squamous intra-epithelial lesion rather than AIS.  The authors concluded that their findings support HPV DNA testing of all AGC specimens to detect cervical, especially squamous, neoplasia.

The American Society for Colposcopy and Cervical Pathology (ASCCP)'s guidelines for the management of women with abnormal cervical cancer screening tests (Wright et al, 2007) noted that HPV testing is incorporated into the management of AGC after their initial evaluation with colposcopy and endometrial sampling.  The recommended post-colposcopy management of women with AGC is to repeat cytologic testing combined with HPV DNA testing at 6 months if they are HPV DNA positive and at 12 months if they are HPV DNA negative.  Referral to colposcopy is recommended for women who subsequently test positive for HPV DNA or who are found to have ASCUS or greater on their repeat cytologic tests.  If both tests are negative, women can return to routine cytologic testing.

In a randomized study, Mayrand et al (2007) examined if testing for DNA of oncogenic HPV is superior to the Pap test for cervical cancer screening.  These investigators compared HPV testing, using an assay approved by the FDA, with conventional Pap testing as a screening method to identify high-grade CIN in women aged 30 to 69 years.  Women with abnormal Pap test results or a positive HPV test (at least 1 pg of high-risk HPV DNA per milliliter) underwent colposcopy and biopsy, as did a random sample of women with negative tests.  Sensitivity and specificity estimates were corrected for verification bias.  A total of 10,154 women were randomly assigned to testing.  Both tests were performed on all women in a randomly assigned sequence at the same session.  The sensitivity of HPV testing for CIN of grade 2 or 3 was 94.6 % (95 % CI: 84.2 to 100), whereas the sensitivity of Pap testing was 55.4 % (95 % CI: 33.6 to 77.2; p = 0.01).  The specificity was 94.1 % (95 % CI: 93.4 to 94.8) for HPV testing and 96.8 % (95 % CI: 96.3 to 97.3; p < 0.001) for Pap testing.  Performance was unaffected by the sequence of the tests.  The sensitivity of both tests used together was 100 %, and the specificity was 92.5 %.  Triage procedures for Pap or HPV testing resulted in fewer referrals for colposcopy than did either test alone but were less sensitive.  No adverse events were reported.  The authors concluded that as compared with Pap testing, HPV testing has greater sensitivity for the detection of CIN.

An assessment by the California Technology Assessment Forum (CTAF, 2008) found HPV testing for primary cervical cancer screening did not meet CTAF criteria.  The CTAF assessment found that, although incorporation of HPV screening can lead to earlier detection of carcinoma in situ lesions, whether or not this will result in reduced cervical cancer incidence and mortality is not known.  The CTAF assessment noted, in addition, that the 2 trials that have published long term follow-up used a PCR test that is not currently available in the United States.  The CTAF assessment concluded that the evidence is insufficient to recommend for or against the incorporation of HPV testing into cervical cancer screening programs.

Thus, whether HPV testing can replace conventional Pap cytologic testing for cervical cancer screening awaits results from randomized controlled trials and/or recommendations from leading national medical organizations.

Sankaranarayanan and colleagues (2009) began to measure the effect of a single round of screening by testing for HPV, cytologic testing, or visual inspection of the cervix with acetic acid (VIA) on the incidence of cervical cancer and the associated rates of death in the Osmanabad district in India.  In this cluster-randomized trial, 52 clusters of villages, with a total of 131,746 healthy women between the ages of 30 and 59 years, were randomly assigned to 4 groups of 13 clusters each.  The groups were randomly assigned to undergo screening by HPV testing (n = 34,126), cytologic testing (n = 32,058), or VIA (n = 34,074) or to receive standard care (n = 31,488, control group).  Women who had positive results on screening underwent colposcopy and directed biopsies, and those with cervical pre-cancerous lesions or cancer received appropriate treatment.  In the HPV-testing group, cervical cancer was diagnosed in 127 subjects (of whom 39 had stage II or higher), as compared with 118 subjects (of whom 82 had advanced disease) in the control group (hazard ratio for the detection of advanced cancer in the HPV-testing group, 0.47; 95 % CI: 0.32 to 0.69).  There were 34 deaths from cancer in the HPV-testing group, as compared with 64 in the control group (hazard ratio, 0.52; 95 % CI: 0.33 to 0.83).  No significant reductions in the numbers of advanced cancers or deaths were observed in the cytologic-testing group or in the VIA group, as compared with the control group.  Mild adverse events were reported in 0.1 % of screened women.  The authors concluded that in a low-resource setting, a single round of HPV testing was associated with a significant reduction in the numbers of advanced cervical cancers and deaths from cervical cancer.

In an editorial that accompanied the afore-mentioned article, Schiffman and Wacholder (2009) stated that "[i]n developed nations, HPV testing at extended screening intervals could eventually replace repeated cytologic testing as the primary screening method.  Cytologic testing might be used to stratify risk further by identifying HPV-positive women at highest risk for cancer.  In these countries, a widespread transition from a good method (frequent cytologic testing) to a better one (less frequent HPV screening) will require high-quality testing that is widely available and properly priced, the establishment of correct screening intervals and related health messages, and the promulgation of clinical guidelines and reimbursement policies to avoid overtreatment of benign infections".  Schiffman and Wacholder also noted that, "[i]n the United States, switching to primary HPV screening will be contentious, partly because lengthening the interval between cervical screenings seriously disrupts established gynecologic clinical practice".

Davis (2009) stated that "[i]n showing that a single round of HPV screening (compared with cytologic or VIA screening) had the most marked effect on preventing cervical cancer deaths, these results have tremendous international health implications: Single rounds of HPV screening are much easier to implement than repetitive cytologic screening, particularly in resource-poor countries where cervical cancer is relatively common.  Nonetheless, we should not rush to apply such findings to populations with optimal resources.  Clinicians in the U.S. should continue to screen as recommended by the American Society for Colposcopy and Cervical Pathology".

Cervicography and Speculoscopy

Cervicography is a procedure in which the cervix is swabbed with an acetic acid solution to identify acetowhite changes in the cervix.  With cervicography, a photograph of the cervix is taken with a special camera (Cerviscope), and is sent to trained technicians for evaluation (National Testing Laboratories, St. Louis, MO).  The technicians determine whether the visual image is most compatible with normal, atypia/metaplasia, intraepithelial neoplasia, or cancer.  In contrast, speculoscopy (PapSure) uses a chemiluminescent light to aid naked-eye or minimally magnified visualization of acetowhite changes on the cervix.  Both cervicography and speculoscopy have been used as an adjunct to Pap smear for cervical cancer screening and as a triage method to identify which patients with low grade atypical Pap smears need further evaluation by colposcopy and biopsy.  According to practice guidelines from the ASCCP, "there have been insufficient large scale controlled studies related to their use in the triage of LGISL [low grade squamous intraepithelial lesion] to recommend either for or against their use" (Cox et al, 2000).  An International Academy of Cytology (IAC) Task Force (van Niekerk et al, 1998) concluded that "[t]he role of cervicography, or high resolution photography, as a screening device remains to be defined."  The IAC Task Force also noted that "[t]here are, at present, insufficient data for the evaluation of speculoscopy…."  The U.S. Preventive Services Task Force (1996) concluded that "[t]here is insufficient evidence to recommend for or against routine screening with cervicography … although recommendations against such screening can be made on other grounds."

Video Colpography

Video colpography (video colposcopy) has been used for imaging the vagina and cervix, and has been proposed for use as a method of cervical cancer screening.  In this procedure, a video camera is used to create computerized digital images of the cervix, vaginal fornices and endocervical canal; the system may be interfaced with a computer for image manipulation.  The images are evaluated by a video screener for signs of cervical cancer.  Etherington et al (1997) stated that video colpography has potential advantages as a portable and rapid method of cervical imaging.  The investigators stated that video colpography has potential of use in fields of teaching, audit and screening of women with low-grade smear abnormalities.  Etherington et al (1997) compared video colpography with colposcopy in a pilot study involving 50 women referred for colposcopy.  The investigators reported that the video colpography images were satisfactory or good in 47 (94 %) cases, and there was agreement between colposcopist and video screener in 86 % of cases.  The investigators stated that, if the technique had been used in a primary health care setting as a secondary screening method for women with low-grade cervical smear abnormalities, 61 % would have avoided referral for colposcopy.  The investigators concluded that "before the technique can be implemented as part of the screening process, it needs to be evaluated in a larger series …"  Other publications have described the technical performance of video colposcopy (e.g., Milbourne et al, 2005) and the use of video colposcopy as a research tool (Brown et al, 2005), as an educational tool (e.g., Walsh et al, 2004), in forensic investigations (e.g., Mears et al, 2003), and in colposcopy quality assurance protocols (e.g., Ferris et al, 2004).  Regarding use of video colposcopy in quality assurance, Ferris et al concluded that "[c]olposcopy quality control by review of digitized colposcopic images in clinical trials warrants further evaluation if the accuracy can be improved."

Optical Detection Systems

The Luma cervical imaging system (MediSpectra, Inc., Lexington, MA) is an optical detection system approved by the FDA in March, 2006 as an adjunct to colposcopy to identify areas of the cervix with the highest likelihood of high-grade CIN on biopsy.  The Luma system shines a light on the cervix and analyzes how different areas of the cervix respond to the light.  The system produces a color map that distinguishes between healthy and potentially diseased tissue to indicate where biopsy samples should be taken.

In a pilot study, Huh and colleagues (2004) investigated the in-vivo optical detection of high-grade CIN.  Cervical scanning devices collected intrinsic fluorescence and broadband white light spectra and video images from 604 women during routine colposcopy examinations.  A statistically significant dataset was developed of intrinsic fluorescence and white light-induced cervical tissue spectra that was correlated to histopathologic determination.  On the basis of a retrospective analysis of the acquired data, a classification algorithm was developed, validated, and optimized.  Intrinsic fluorescence, back-scattered white light, and video imaging each contributed complementary information to diagnostic algorithms for high-grade cervical neoplasia.  Over 10,000 measurements were made on colposcopically identified tissue from more than 500 subjects and were the basis for algorithm training and testing.  Algorithm performance demonstrated a sensitivity of approximately 90 %.  This performance was confirmed by various training methods.  With the use of a multi-variate classification algorithm, optical detection is predicted to detect 33 % more high-grade CIN (2/3+) than colposcopy alone.  The authors concluded that full cervix optical interrogation for the detection of high-grade CIN is feasible and appears capable of detecting more high-grade CIN than colposcopy alone. 

A multi-center controlled trial (Alvarez et al, 2007) evaluated the performance of the Luma system as an adjunct to colposcopy among women (n = 193) referred for the evaluation of an abnormal cervical cytology result.  Initial colposcopy identified 41 cases of CIN 2+ for a true positive (TP) rate of 21.2 %.  Adjunctive use of the Luma system identified an additional 9 cases of CIN 2+ which corresponds to an incremental optical detection TP rate of 4.7 % (95 % CI: 2.2 % to 8.7 %).  Adjunctive use of the Luma system resulted in a 22.0 % (95 % CI: 6.1 % to 37.8 %) relative gain in the number of women with CIN 2+ compared to colposcopy alone.  The false-positive (FP) rate for initial colposcopy was 51.8 % (100 of 193 women).  An additional 35 subjects had a Luma system-directed biopsy that was not diagnosed as CIN 2+, yielding an incremental FP rate of 18.1 % (95 % CI: 13.0 % to 24.3 %).  The authors concluded that the adjunctive use of the Luma system with colposcopy provided a significant increase in the detection of CIN 2+ in women referred for the evaluation of abnormal cytology results. 

There is insufficient evidence of the effectiveness of an optical detection system as an adjunct to colposcopy for in vivo identification and localization of cervical intraepithelial for cervical cancer screening or diagnosis.  Furthermore, there are no recommendations or guidelines for its use from any professional medical society.  Post-approval studies are currently underway to further assess the long-term efficacy of the Luma system.

ResolveTM 

Colposcopy is a diagnostic procedure in which a colposcope is used to provide an illuminated, magnified view of the cervix, vagina, and vulva to detect malignant and pre-malignant epithelium.  Malignant and pre-malignant epithelium have specific macroscopic characteristics relating to contour, color, and vascular pattern that can be identified by the colposcopist for directed biopsy.  Colposcopy is the "gold standard" diagnostic tool in the U.S. for diagnosing cervical dysplasia following abnormal cytology.

The Resolve laboratory testing kit (Gynecor, Glen Allen, VA) is a new colposcopic method that obtains endocervical samples using cytobrushes.  The kit contains 2 cytobrushes and 2 vials of fixative.  The 1st cytobrush is used to clear mucus from the cervix and the 2nd cytobrush is used to abrade cells from the endocervix.  The fixative enables both cytology and histology to be run on both vials.  HPV is also tested from the same specimen.  If HPV is detected, genotyping by PCR is also reported.

There is insufficient evidence of the effectiveness of the Resolve laboratory testing kit for cervical cancer screening or diagnosis.  How this method compares with conventional colposcopy and cytology using quantified values of sensitivity and specificity awaits results from randomized controlled trials and/or recommendations from leading national medical organizations.

Methylation Markers

Studies of cervical cancer and its immediate precursor, cervical intra-epithelial neoplasia 3, have identified genes that often show aberrant DNA methylation and thus represent candidate early detection markers.  Wentzensen et al (2009) identified the most promising methylation marker candidates for cervical cancer early detection.  A systematic literature review was performed in Medline and weighted average frequencies for methylated genes stratified by tissue source and methods used were computed.  A total of 51 studies were identified analyzing 68 different genes for methylation in 4,376 specimens across all stages of cervical carcinogenesis.  A total of 15 genes (DAPK1, RASSF1, CDH1, CDKN2A, MGMT, RARB, APC, FHIT, MLH1, TIMP3, GSTP1, CADM1, CDH13, HIC1, and TERT) have been analyzed in 5 or more studies.  The published data on these genes is highly heterogeneous; 7 genes (CDH1, FHIT, TERT, CDH13, MGMT, TIMP3, and HIC1) had a reported range of methylation frequencies in cervical cancers of greater than 60 % between studies.  Stratification by analysis method did not resolve the heterogeneity.  Three markers (DAPK1, CADM1, and RARB) showed elevated methylation in cervical cancers consistently across studies.  The authors concluded that there is currently no methylation marker that can be readily translated for use in cervical cancer screening or triage settings.  They stated that large, well-conducted methylation profiling studies of cervical carcinogenesis could yield new candidates that are more specific for HPV-related carcinogenesis.  New candidate markers need to be thoroughly validated in highly standardized assays.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
Annual cervical cancer screening with Papanicolaou (Pap) smears (21 years of age and older):
CPT codes covered if selection criteria are met:
88141
88142
88143
88147
88148
88150
88152
88153
88154
+ 88155
88164
88165
88166
88167
88174
88175
HCPCS codes covered if selection criteria are met:
G0101 Cervical or vaginal cancer screening; pelvic and clinical breast examination
G0123 Screening cytopathology, cervical or vaginal (any reporting system), collected in preservative fluid, automated thin layer preparation; screening by cytotechnologist under physician supervision
G0124     requiring interpretation by physician
G0141 Screening cytopathology smears, cervical or vaginal, performed by automated system, with manual rescreening, requiring interpretation by physician
G0143 Screening cytopathology, cervical or vaginal (any reporting system), collected in preservative fluid, automated thin layer preparation; with manual screening and rescreening by cytotechnologist under physician supervision,
G0144     with screening by automated system, under physician supervision
G0145 Screening cytopathology, cervical or vaginal (any reporting system), collected in preservative fluid, automated thin layer preparation, with screening by automated system and manual rescreening under physician supervision
G0147 Screening cytopathology smears, cervical or vaginal; performed by automated system under physician supervision
G0148     performed by automated system with manual rescreening
P3000 Screening papanicolaou smear, cervical or vaginal, up to three smears; by technician under physician supervision
P3001     requiring interpretation by physician
Q0091 Screening papanicolaou smear; obtaining, preparing and conveyance of cervical or vaginal smear to laboratory
ICD-9 codes covered if selection criteria are met:
042 Human immunodeficiency virus [HIV] disease
079.4 Human papillomavirus [HPV]
090.0 - 099.9 Syphilis and other venereal diseases
131.00 - 131.09 Other urogenital trichomoniasis
179 - 184.9 Malignant neoplasm of female genital organs
198.82 Secondary malignant neoplasm of genital organs
198.6 Secondary malignant neoplasm of ovary
233.1 - 233.39 Carcinoma in situ of female genital organs
236.3 Neoplasm of uncertain behavior of female genital organs
279.00 - 279.9 Disorders involving the immune mechanism [immunosuppression]
616.0 Cervicitis and endocervicitis
616.81 Mucositis (ulcerative) of cervix, vagina, and vulva
622.10 - 622.12 Dysplasia of cervix (uteri)
623.5 Leukorrhea, not specified as infective [abnormal discharge]
623.8 Other specified noninflammatory disorders of vagina [abnormal bleeding]
626.8 Other disorders of menstruation and other abnormal bleeding from female genital tract
795.00 - 795.09 Abnormal Papanicolaou smear of cervix and cervical HPV
E932.2 Adverse effects of ovarian hormones and synthetic substitutes [exposure to DES]
V08 Asymptomatic human immunodeficiency virus [HIV] infection status
V10.40 - V10.44 Personal history of malignant neoplasm of female genital organs
V13.29 Personal history of other genital system and obstetric disorders
V69.2 High-risk sexual behavior [multiple sexual partners]
V71.1 Observation for suspected malignant neoplasm
V72.31 Routine gynecological examination
V76.2 Special screening for malignant neoplasm of cervix
ICD-9 codes not covered for indications listed in the CPB:
752.49 Other anomalies of cervix, vagina, and external female genitalia [congenital absence of cervix]
V88.01 Acquired absence of both cervix and uterus
V88.03 Acquired absence of cervix with remaining uterus
Annual cervical cancer screening with Papanicolaou (Pap) smears (under 21 years of age):
CPT codes covered if selection criteria are met:
88141
88142
88143
88147
88148
88150
88152
88153
88154
+88155
88164
88165
88166
88167
88174
88175
HCPCS codes covered if selection criteria are met:
P3000 Screening papanicolaou smear, cervical or vaginal, up to three smears; by technician under physician supervision
P3001     requiring interpretation by physician
HCPCS codes not covered for indications listed in the CPB (routine/preventive):
G0123 Screening cytopathology, cervical or vaginal (any reporting system), collected in preservative fluid, automated thin layer preparation; screening by cytotechnologist under physician supervision
G0124     requiring interpretation by physician
G0141 Screening cytopathology smears, cervical or vaginal, performed by automated system, with manual rescreening, requiring interpretation by physician
G0143 Screening cytopathology, cervical or vaginal (any reporting system), collected in preservative fluid, automated thin layer preparation; with manual screening and rescreening by cytotechnologist under physician supervision
G0144     with screening by automated system, under physician supervision
G0145 Screening cytopathology, cervical or vaginal (any reporting system), collected in preservative fluid, automated thin layer preparation, with screening by automated system and manual rescreening under physician supervision
G0147 Screening cytopathology smears, cervical or vaginal; performed by automated system under physician supervision
G0148     performed by automated system with manual rescreening
Q0091 Screening papanicolaou smear; obtaining, preparing and conveyance of cervical or vaginal smear to laboratory
ICD-9 codes covered if selection criteria are met:
042 Human immunodeficiency virus (HIV) disease
079.53 Human immunodeficiency virus type 2 [HIV-2]
180.0 - 180.9 Malignant neoplasm of cervix uteri
233.1 Carcinoma in situ of cervix uteri
622.10 - 622.12 Dysplasia of cervix uteri
647.60 - 647.64 Other viral diseases complicating pregnancy, childbirth, or the puerperium
795.00 Abnormal glandular Papanicolaou smear of cervix
795.01 Papanicolaou smear of cervix with atypical squamous cells of undetermined significance (ASC-US)
795.02 Papanicolaou smear of cervix with atypical squamous cells cannot exclude high grade squamous intraepithelial lesion (ASC-H)
795.03 Papanicolaou smear of cervix with low grade squamous intraepithelial lesion (LGSIL)
795.04 Papanicolaou smear of cervix with high grade squamous intraepithelial lesion (HGSIL)
795.06 Papanicolaou smear of cervix with cytologic evidence of malignancy
795.71 Nonspecific serologic evidence of human immunodeficiency virus (HIV)
V01.79 Contact with or exposure to other viral diseases
V08 Asymptomatic human immunodeficiency virus (HIV) infection status
V10.41 Personal history of malignant neoplasm of cervix uteri
V13.22 Personal history of cervical dysplasia
V42.0 - V42.9 Organ or tissue replaced by transplant
HPV testing in women 21 to 30 years of age (not covered under 21 years of age):
CPT codes covered if selection criteria are met:
87620
87621
ICD-9 codes covered if selection criteria are met (all-inclusive):
795.00 Abnormal glandular Papanicolaou smear of cervix [atypical cervical glandular cells]
795.01 Papanicolaou smear of cervix with atypical squamous cells of undetermined significance (ASC-US)
795.02 Papanicolaou smear of cervix with atypical squamous cells cannot exclude high grade squamous intraepithelial lesion (ASC-H)
795.03 Papanicolaou smear of cervix with low grade squamous intraepithelial lesion (LGSIL)
795.04 Papanicolaou smear of cervix with high grade squamous intraepithelial lesion (HGSIL)
795.05 Cervical high risk human papillomavirus (HPV) DNA positive
V72.32 Encounter for Papanicolaou cervical smear to confirm findings of recent normal smear following initial abnormal smear
Cervicography or speculoscopy (Pap-Sure):
There is no specific code for cervicography or speculoscopy:
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
180.0 - 180.9 Malignant neoplasm of cervix uteri
233.1 Carcinoma in situ of cervix uteri
V76.2 Special screening for malignant neoplasm of cervix
Methylation markers for cervical cancer screening:
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
180.0 - 180.9 Malignant neoplasm of cervix uteri
233.1 Carcinoma in situ of cervix uteri
V76.2 Special screening for malignant neoplasm of cervix


The above policy is based on the following references:
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