ThinPrep Diagnostic with Human Papillomavirus (HPV) Reflex
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Squamous cell carcinoma of the cervix is believed to develop in progressive stages from normal through precancerous (dysplastic) stages, to carcinoma in situ, and eventually invasive carcinoma. This sequence is felt to develop over a matter of years in most patients.
Follow up of the cervical Pap abnormality "atypical squamous cells of undetermined significance (ASCUS)" is costly and frustrating to patients and clinicians because a large percentage of these patients have normal colposcopic and biopsy findings. Yet, a significant percentage (10%-15%) will have an underlying high-grade squamous intraepithelial lesion (HSIL).
The majority (>99%) of cervical epithelial neoplasms are the result of human papillomavirus (HPV) infection. "High-risk" HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) can result in both low-grade squamous intraepithelial lesions and HSIL, as well as invasive carcinomas. Patients with HSIL have a greater risk for progression to carcinoma.
In the setting of an abnormal Pap result, the presence of high-risk HPV types in cervical specimens identifies a subgroup of patients with a greater likelihood of having a HSIL.
If the patient has been previously diagnosed with an abnormal Pap result or is at high risk, considering ordering this test, which is diagnostic, rather than the screen (83342 / ThinPrep Screen with Human Papillomavirus [HPV] Reflex).
Persistent infection with HPV is the principal cause of cervical cancer and its precursor cervical intraepithelial neoplasia (CIN).(1-3) The presence of HPV has been implicated in >99% of cervical cancers worldwide. HPV is a small, non-enveloped, double-stranded DNA virus, with a genome of approximately 8,000 nucleotides. There are more than 118 different types of HPV and approximately 40 different HPVs that can infect the human anogenital mucosa. However, data suggest that 14 of these types (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68) are considered high-risk (HR) for the development of cervical cancer and its precursor lesions. Furthermore, HPV types 16 and 18 have been regarded as the genotypes most closely associated with progression to cervical cancer. HPV-16 is the most carcinogenic, and is associated with approximately 60% of all cervical cancers, while HPV-18 accounts for approximately 10% to 15% of cervical cancers.(4, 6-7)
Although persistent infection with HR HPV is necessary for the development of cervical cancer and its precursor lesions, only a very small percentage of infections progress to these disease states. Sexually transmitted infection with HPV is extremely common, with estimates of up to 75% of all women being exposed to HPV at some point. However, almost all infected women will mount an effective immune response and clear the infection within 2 years without any long term health consequences. An infection with any HPV type can produce CIN although this also usually resolves once the HPV infection has been cleared.
In developed countries with cervical cancer screening programs, the Pap smear has been used since the mid-1950s as the primary tool to detect early precursors to cervical cancer. Although it has decreased the death rates due to cervical cancer dramatically in those countries, the Pap smear and subsequent liquid based cytology methods require subjective interpretation by highly trained cytopathologists and misinterpretation can occur. Cytological abnormalities are primarily due to infection with HPV; however, various inflammatory conditions or sampling variations can result in false-positive cytology results. Triage of an abnormal cytology result may involve repeat testing, colposcopy and/or biopsy. A histologically confirmed high-grade lesion must be surgically removed or ablated in order to prevent the development of invasive cervical cancer.
Nucleic acid (DNA) testing by PCR has become a standard, noninvasive method for determining the presence of a cervical HPV infection. Proper implementation of nucleic acid testing for HPV may 1) increase the sensitivity of cervical cancer screening programs by detecting high-risk lesions earlier in women 30 years and older with normal cytology and 2) reduce the need for unnecessary colposcopy and treatment in patients 21 and older with cytology results showing atypical squamous cells of undetermined significance (ASC-US).
Recently, data suggest that individual genotyping for HPV types 16 and 18 can assist in determining appropriate follow-up testing and triaging women at risk for progression to cervical cancer. Studies have shown that the absolute risk of CIN-2 or worse in HPV-16 and/or HPV-18 positive women is 11.4% (95% confidence interval [CI] 8.4%-14.8%) compared with 6.1% (95% CI, 4.9%-7.2%) of women positive for 'other' HR-HPV genotypes and 0.8% (95% CI, 0.3%-1.5%) in HR-HPV negative women.(8) Based in part on these data, the American Society for Colposcopy and Cervical Pathology (ASCCP) now recommends that HPV 16/18 genotyping be performed on women that are positive for HR-HPV but negative by routine cytology. Women that are found to be positive for HPV-16 and/or -18 may be referred to colposcopy, while women that are negative for genotypes 16 and/or 18 may have repeat cytology and HR HPV testing in 12 months.(4)
Management and triage of patient's, age 21 or greater, with abnormal Pap results
HPV testing detection of high risk genotypes associated with the development of cervical cancer
Results can be used as an aid in triaging women with abnormal Pap smear results
Individual genotyping of HPV-16 and/or HPV-18, if present
Results of HPV-16 and HPV-18 genotyping can be used as an aid in triaging women with positive HR-HPV but negative Pap smear results.
Standard reporting, as defined by the Bethesda System (TBS) is utilized.
Human papillomavirus (HPV):
A positive result indicates the presence of HPV DNA due to 1 or more of the following genotypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68.
A negative result indicates the absence of HPV DNA of the targeted genotypes.
For patients with atypical squamous cells of undetermined significance (ASC-US) Pap smear result and who are positive for high-risk (HR) HPV, consider referral for colposcopy, if clinically indicated.
For women aged 30 years and older with a negative Pap smear result but who are positive for HPV-16 and/or HPV-18, consider referral for colposcopy, if clinically indicated.
For women aged 30 years and older with a negative Pap smear, positive high-risk HPV test result, but who are negative for HPV-16 and HPV-18, consider repeat testing by both cytology and a HR HPV test in 12 months.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
The Pap test is a screening test for cervical cancer with inherent false-negative results. A negative human papillomavirus (HPV) test or Pap smear result does not preclude the presence of carcinoma or intraepithelial lesion. The false-negative rates of the Pap test range from 15% to 30%.
The cobas HPV test detects DNA of the high-risk types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68. This test does not detect DNA of HPV low-risk types (eg, 6, 11, 42, 43, 44) since these are not associated with cervical cancer and its precursor lesions.
The cobas HPV test is not recommended for evaluation of suspected sexual abuse.
Prevalence of HPV infection in a population may affect performance. Positive predictive values decrease when testing populations with low prevalence or individuals with no risk of infection.
Infection with HPV is not an indicator of cytologic high grade intraepithelial lesion (HSIL) or underlying high-grade cervical intraepithelial neoplasia (CIN), nor does it imply that CIN2-3 or cancer will develop. Most women infected with 1 or more high-risk (HR) HPV types do not develop CIN2-3 or cancer.
A negative HR HPV result does not exclude the possibility of future cytologic HSIL or underlying CIN2-3 or cancer.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
ThinPrep Pap Test:
Satisfactory for evaluation. Negative for intraepithelial lesion or malignancy.
Note: Abnormal results will be reviewed by a pathologist at an additional charge.
Negative for HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Solomon D, Schiffman M, Tarone R: Comparison of three management strategies for patients with atypical squamous cells of undetermined significance: baseline results from a randomized trial. J Natl Cancer Inst 2001;93:293-299
2. Soloman D, Davey D, Kurman R, et al: The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002;287:2114-2119
3. Wright TC, Cox JT, Massad LS, et al: 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA 2002;287:2120-21294.
4. Saslow D, Solomon D, Lawson HW, et al: American Cancer Society, American Society for Colposclpy and Cervical Pathology, and American Society for Clinical Pathology Screening Guidelines for the Prevention and Early Detection of Cervical Cancer. J Low Genit Tract Dis 2012;16(3):175-204
5. Procedure manual and package insert: cobas HPV test. Roche Diagnostics. Indianapolis, IN, version 05641268001-01EN
6. Walboomers JM, Jacobs MV, Manos MM, et al: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12-19
7. de Sanjose S, Quint WG, Alemany L, et al: Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010;11:1048-1056
8. Wright TC Jr, Stoler MH, Sharma A, et al: Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV positive, cytology-negative results. Am J Clin Pathol 2011 Oct;136(4):578-586
9. Massad LS, Einstein MH, Huh WK, et al: 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2013 April;17(5 Suppl 1):S1-S27
10. Sherman ME, Lorincz A, Scott DR, et al: Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Nat Cancer Inst 2003 January;95(1):46-52