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HPV RNA, High Risk, E6/E7, TMA

HPV RNA, High Risk, E6/E7, TMA

Test Summary

HPV RNA, High Risk, E6/E7, TMA

  

Clinical Use

  • Screen for cervical cancer in women 30-65 years of age (in conjunction with cervical cytology)

  • Determine need for colposcopy in women 21-29 years of age with ASC-US (atypical squamous cells of uncertain significance) cervical cytology results

Clinical Background

Human papilloma virus (HPV) infection has been shown to be the etiological agent in more than 99% of cervical cancers.1 Of the more than 100 HPV genotypes, 14 have been linked to the development of cervical cancer and are therefore termed high-risk genotypes.2 Although the majority of HPV infections spontaneously resolve within 2 years, individuals with persistent high-risk HPV infection are at high risk of developing cervical intraepithelial neoplasia (CIN) and cervical carcinoma.2,3

Cervical cytology (ie, Pap test) has been used to screen for premalignant and malignant cervical lesions since its introduction in the 1950s, and its use has reduced the incidence of cervical cancer; however, it is limited by relatively low sensitivity and specificity.4 Numerous studies have shown that testing for high-risk HPV DNA is significantly more sensitive (high negative predictive value) than cytology for the detection of high-grade CIN (ie, CIN 2 or greater).5,6 Though current high-risk HPV DNA testing methods provide adequate sensitivity, specificity is lacking (low positive predictive value) leading to false-positive results and unnecessary invasive procedures such as colposcopy and biopsy.7

HPV E6/E7 oncoproteins mediate the development of cervical cancer. Their overexpression, which can be measured as E6/E7 messenger RNA (mRNA) transcripts, is associated with a significantly increased risk of CIN and cervical cancer.8,9 This test determines the presence of E6/E7 mRNA from 14 high-risk HPV genotypes.

In a study of 800 women referred for colposcopy, the sensitivity and specificity of this test were shown to be >92% and 99%, respectively, for detection of high-risk HPV types and 91% and >55%, respectively, for the detection of CIN2+.10 In women undergoing routine screening (N=1,373), the sensitivity and specificity for the detection of CIN2+ were 100% and 88.3%, respectively.11

Individuals Suitable for Testing

  • Women 30-65 years of age

  • Women 21-29 years of age who have an ASC-US, LSIL, or more severe cervical cytology result

Method

  • Transcription-mediated amplification (TMA)

–   Detects E6/E7 mRNA from 14 high-risk HPV genotypes

  • Analytical sensitivity:

–  <100 copies mRNA/reaction (types 16, 18, 31, 33, 35, 39, 45, 58, 59, 66, 68)

–   100-300 copies mRNA/reaction (types 51, 52, 56)

  • Analytical specificity: cross-reacts with low-risk HPV genotypes 26, 67, 70 and 82, but not with any bacteria, yeast, or fungi tested

  • Results reported: HPV mRNA detected or not detected; does not differentiate the genotypes

Interpretive Information

A “not detected” result is consistent with the absence of high-risk HPV E6/E7 mRNA, a level of HPV DNA below the detection limit of the assay, or presence of a genotype other than those listed above. It suggests a low risk of cervical cancer.

A “detected” result indicates the presence of high-risk HPV E6/E7 mRNA and is suggestive of an increased risk of cervical cancer.

Results may be affected by polyquaternium 15 (found in personal lubricants) and by the antifungal tioconazole. Performance in HPV-vaccinated women has not been evaluated. Results should be interpreted in conjunction with other clinical and laboratory data.

Below is a summary of follow-up recommendations for specific combinations of HPV and cervical cytology results.12 Guidelines do not distinguish between high-risk HPV testing methods, which may have variable sensitivity and specificity.

Age 30-65 years

  • Pap test negative or ASC-US/high-risk HPV negative: Routine screening with Pap and high-risk HPV at 5-year intervals (preferred)

  • Pap test negative/high-risk HPV positive: Repeat Pap test and high-risk HPV test at 12 months; or perform HPV genotype 16, 18 test

  • Pap test ASC-US/ high-risk HPV positive: Colposcopy

  • Pap test ASC-H, LSIL, HSIL, cancer: Colposcopy

Age 21-29

  • Pap test ASC-US/ high-risk HPV negative: Routine screening with Pap test at 3-year intervals

  • Pap test ASC-US/ high-risk HPV positive: Colposcopy

  • Pap test ASC-H, LSIL, HSIL, cancer: Colposcopy

References

  1. Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond). 2006;110(5):525-541.

  2. Li N, Franceschi S, Howell-Jones R, et al. Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: Variation by geographical region, histological type and year of publication. Int J Cancer. 2011;128:927-935.

  3. Kjaer SK, van den Brule AJ, Paull G, et al. Type specific persistence of high risk human papillomavirus (HPV) as indicator of high grade cervical squamous intraepithelial lesions in young women: population based prospective follow up study. BMJ. 2002;325:572-579.

  4. Cong X, Cox DD, Cantor SB. Bayesian meta-analysis of Papanicolaou smear accuracy. Gynecol Oncol. 2007;107(Suppl 1):S133-S137.

  5. Mayrand MH, Duarte-Franco E, Rodrigues I, et al for the Canadian Cervical Cancer Screening Trial Study Group. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med. 2007;357:1579-1588.

  6. Ronco G, Giorgi-Rossi P, Carozzi F, et al for the New Technologies for Cervical Cancer Screening Working Group. Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test. J Natl Cancer Inst. 2008:100;492-501.

  7. Castle PE, Solomon D, Wheeler CM, et al. Human papillomavirus genotype specificity of Hybrid Capture 2. J Clin Microbiol. 2008;46:2595-2604.

  8. Cuschieri KS, Whitley MJ, Cubie HA. Human papillomavirus type specific DNA and RNA persistence–implications for cervical disease progression and monitoring. J Med Virol. 2004;73:65-70.

  9. Monsonego J, Hudgens MG, Zerat L, et al. Risk assessment and clinical impact of liquid-based cytology, oncogenic human papillomavirus (HPV) DNA and mRNA testing in primary cervical cancer screening (The FASE Study). 2012;125:175-180. Gynecol Oncol.

  10. Dockter J, Schroder A, Hill C, et al. Clinical performance of the APTIMA HPV assay for the detection of high-risk HPV and high-grade cervical lesions. J Clin Virol. 2009;45(Suppl 1):S55-S61.

  11. Ratnam S, Coutlee F, Fontaine D, et al. Aptima HPV E6/E7 mRNA test is as sensitive as Hybrid Capture 2 assay but more specific at detecting cervical precancer and cancer. J Clin Microbiol. 2011;49:557-564.

  12. Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol. 2012;137:516-542.

  13. Wright TC Jr, Massad LS, Dunton CJ, et al; 2006 ASCCP-Sponsored Consensus Conference. 2006 consensus guidelines for the management of women with abnormal cervical screening tests. J Low Genit Tract Dis. 2007;11:201-222. Erratum in: J Low Genit Tract Dis. 2008;12:255.
     
 Content reviewed 12/2012

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