HPV testing: is it useful in triage of minor Pap abnormalities?
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Biomedical subjects
Publications and source records attributed to J T Cox.
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The subjectivity of morphologic methods contributes to a "swamping" of colposcopic services, excessive costs, overdiagnosis, and overtreatment. HPV DNA testing provides the objectivity required to clarify difficult patient management issues, including follow-up, for low-grade cytologic abnormalities (ASCUS and LSIL), noncorrelating (nonconfirmed) Pap smears, evaluation of nondiagnostic lower genital tract lesions, and cytology and histology laboratory quality assurance. Additionally, favorable preliminary data on HPV testing as a primary screen raise the exciting prospect of potentially lowering costs of cervical cancer-screening programs, while further decreasing the incidence of cervical cancer.
Proper evaluation of the vulva required background in general dermatology and an understanding of the special nature of many vulvar conditions. A firm understanding of normal vulvar findings is necessary to guard against overdiagnosis and unnecessary treatment. In the past few years, the most common overdiagnosis has been that of micropapillae of the inner labia minora, or acetowhite changes of the vulva, secondary to human papillomavirus (HPV) infection. Differentiating normal variants and minor nonspecific findings from well-developed disease is not always easy. Vulvar biopsy should be performed if a diagnosis cannot be made confidently by visual inspection alone. Vulvar intraepithelial neoplasia is a precancerous lesion of squamous origin associated with HPV infection. It usually occurs in younger patients. Vulvar intraepithelial neoplasia in older women is associated with chronic inflammation, especially in areas of hyperplasia and atrophy. The older patient with vulvar intraepithelial neoplasia has a higher risk of developing invasive vulvar cancer.
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OBJECTIVE: Our purpose was to determine the clinical value of human papillomavirus deoxyribonucleic acid testing with the hybrid capture test, specifically to examine whether human papillomavirus testing could identify which women with Papanicolaou smears read as atypical squamous cells of undetermined significance were most likely to have histologically confirmed cervical intraepithelial neoplasia. STUDY DESIGN: Hybrid capture testing for 14 human papillomavirus types, repeat Papanicolaou smears, and colposcopically directed biopsies were performed concurrently on 217 women referred to a student health colposcopy clinic with a previous Papanicolaou smear read as atypical squamous cells of undetermined significance. RESULTS: Human papillomavirus deoxyribonucleic acid positivity was associated with an eightfold increased likelihood of histologic confirmation of cervical intraepithelial neoplasia. The sensitivity of hybrid capture for any cervical intraepithelial neoplasia was 86% (43/50) and for grade 2 or 3 was 93% (14/15), whereas the corresponding values for the repeat Papanicolaou smear were 60% (30/50) and 73% (11/15), respectively. Moreover, high viral levels of human papillomavirus types known to be associated with cervical cancer were strongly predictive of high-grade cervical intraepithelial neoplasia. CONCLUSIONS: Testing for human papillomavirus deoxyribonucleic acid with hybrid capture appears to offer an effective means by which patients whose cervical Papanicolaou smears have been read as atypical squamous cells of undetermined significance could be triaged for colposcopy. In particular, sensitivity for high-grade cervical intraepithelial neoplasia could be maintained and specificity markedly improved by referring only those patients who had elevated levels of human papillomavirus deoxyribonucleic acid of cancer-associated viral types.
The evidence implicating specific HPV types in the aetiology of cervical cancer is now strong enough to establish a causative role. HPV infection of the cervix affects the developing immature metaplastic cells of the transformation zone. Cervical neoplasia can be viewed as the interaction of high risk papillomavirus and immature metaplastic epithelium. Once maturity is reached, there is minimal risk of subsequent development of cervical squamous neoplasia. Exposure to HPV is an extremely common event, especially in young sexually active women. Yet, despite frequent HPV exposure at that phase of life in which the cervical transformation zone is at its most vulnerable, established expressed disease is relatively uncommon. Most studies in which the natural history of CIN is not altered by cervical biopsy reveal a progression rate from low to high grade CIN of less than one third. Where viral type is taken into account, however, the progression rate from normal but high risk HPV-infected cervical epithelium to CIN 2 or 3 is higher. Despite this, most cervical abnormalities will not transform into invasive cancer, even if left untreated. The variance between the high rate of HPV infection, the intermediate rate of CIN and the relatively low rate of cervical cancer establishes a stepwise gradient of disease of increasing severity with decreasing prevalence. In an immunocompetent host, HPV infection alone does not appear to be sufficient to induce the step from high grade CIN to invasion. Epidemiological studies indicating that HPV infection with oncogenic viral types is far more common than cervical neoplasia suggest the necessity of cofactors in cervical carcinogenesis. The long time-lag between initial infection and eventual malignant conversion suggests that random events may be necessary for such conversion, and the spontaneous regression of many primary lesions suggests that most patients are not exposed to these random events. Potential cofactors include cigarette smoking, hormonal effects of oral contraceptives and pregnancy, dietary deficiencies, immunosuppression and chronic inflammation. In those women who develop cervical cancer, malignant progression is rarely rapid, more commonly taking many years or decades. Malignant progression has been documented in patients who presented initially with only low grade HPV-induced atypia. On the other hand, progression may be a misnomer, as 'apparent' progression may really represent adjacent 'de novo' development of higher grade CIN. Although most cervical cancers contain high risk HPV types, up to 15% of such cancers test negative for HPV, raising the possibility that a few, usually more aggressive, cervical cancers may arise from from a non-viral source.(ABSTRACT TRUNCATED AT 400 WORDS)
OBJECTIVE: To determine the usefulness of human papillomavirus (HPV) testing as a triage method for predicting which women referred to a colposcopy clinic were most likely to have histologically confirmed cervical intraepithelial neoplasia (CIN). METHODS: Papanicolaou tests, ViraPap tests for HPV infection, and colposcopically directed biopsies were performed concurrently on 482 women referred to a student health colposcopy clinic. RESULTS: The results demonstrated that HPV positivity was associated with a greatly increased likelihood of histologic confirmation of CIN, especially among women with concurrent cytologic findings that were negative or showed only atypical squamous cells of undetermined significance. CONCLUSIONS: Testing for HPV appears to have a role in the triage of students now being referred to our colposcopy clinic. A combination of HPV testing and repeated cytologic screening would provide reasonably sensitive screening for cervical neoplasia while limiting the use of colposcopic services, which are currently overburdened. The eventual usefulness of HPV testing will depend on the cost and availability of colposcopy services, the cost of Papanicolaou tests, the cost and accuracy of HPV tests, and the predictive value of HPV detection in the population being screened.
Guaymi Indian children have recently been identified as a population group who are at risk for vitamin A deficiency with numerous cases of xerophthalmia with ocular perforation being reported. A four-day parasitological and nutritional clinic based survey was conducted with 335 Guaymi women and children in the towns of San Felix and Alto Caballero to identify the prevalence of parasitic infections and factors associated with malnutrition. A subsample of 79 children, under 19 years of age, from independent families was constructed for the current analysis. The results of the study indicated that 20% of the children had a plasma vitamin A concentration less than 20 micrograms/dl. Significant associations were identified between ascariasis, age, a food diversity score and vitamin A concentrations. Other indicators of nutritional status were also negatively associated with intestinal parasitic infections, and a modernization index, using multivariate regression analysis. In conclusion, this study identified several factors associated with poor nutritional status that can be used by health officers to identify Guaymi children at risk for malnutrition.
Two oral contraceptive steroids, mestranol and norethynodrel, were evaluated for mutagenicity in the Salmonella histidine reversion assay. The pure forms of the hormones were not mutagenic when tested with either missense (TA1535, TA100) or frameshift (TA98, TA1538, TA1537) strains. In vitro activation of the hormones with liver homogenates from rats induced either with phenobarbital or Aroclor did not influence these results. However, mestranol was capable of enhancing the mutation yield obtained by an ineffective subthreshold dose of 2-acetylaminofluorene. Dimethyl sulfoxide extracts of two contraceptive pills, Ovulen-21 (containing mestranol) or Enovid-E (containing mestranol or norethynodrel), also were nonmutagenic. But again, both these extracts were capable of enhancing the mutation yield induced with an ineffective dosage of 2-acetylaminofluorene and N-nitrosopiperidine. These studies point to the possible promotional effect and subsequent potential hazard to the female consumers who use these hormones as a means of pregnancy control.
The mutagenicity of nitrosopyrrolidine (NPYR) and its derivatives was determined by use of the Ames Salmonella assay. A clear specificity to revert the missense stain of TA1535 and a requirement for the phenobarbital-induced rat-liver activation system (S9 mix) were noted. 3,4-Dichloronitrosopyrrolidine was more mutagenic than NPYR, whereas 3-hydroxynitrosopyrrolidine was weakly mutagenic. The carcinogenic nitroso-3-pyrrolidine was not mutagenic under the test conditions. The noncarcinogenic derivatives (2,5-dimethylnitrosopyrrolidine, nitrosoproline and 4-hydroxynitrosoproline) were not mutagenic. Liquid preincubation assays were not any more effective than the pour-plate assays. Selected derivatives of NPYR were tested in the Escherichia coli K-12 (343/113) assay A specificity to revert the missense mutation at the arg locus and a dependence on phenobarbital-induced rat-liver S9 mix were noted with NPYR and its derivatives. 3,4-Dibromonitrosopyrrolidine, which was not mutagenic in Salmonella, was effective in E. coli, and the weakly carcinogenic NPRL was a weak mutagen resulting in a 2-fold enhancement in the E. coli arginine reversion assay.
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