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Chapter 14: Role of triage testing in cervical cancer screening.

The classic model of cervical cancer prevention-primary screening with cytology, followed by diagnostic colposcopically directed biopsy, and finally treatment of cancer precursors-is undergoing dynamic change. The introduction of human papillomavirus (HPV) DNA testing and other new modalities provides more options but increases complexity in the sequence of screening, triage, diagnosis, and patient management. This chapter will focus on the role of triage and risk stratification in management. The utility of HPV testing has been established for triage of cytologic findings of atypical squamous cells of undetermined significance but not for low-grade squamous intraepithelial lesions or worse. Countries without established cytology services may consider alternative screening, triage, and treatment programs that may be more readily implemented than a resource-rich "cytology followed by colposcopy" paradigm requiring an infrastructure of highly trained personnel. The diagnostic step of colposcopy and directed biopsy is not completely sensitive in the detection of cervical intraepithelial neoplasia (CIN) 2 or 3 as is sometimes assumed. The partial insensitivity of this diagnostic step results in a population of women with negative colposcopically directed-biopsy findings but at increased risk for missed prevalent disease: these women may require additional triage rather than resumption of routine screening. As more efficient screening, triage, and diagnosis increase the sensitivity of detection of even very small CIN2 or CIN3, overtreatment of lesions that might otherwise regress becomes a concern and highlights the need to identify accurate markers of risk of progression to cancer. Markers of molecular events further along the pathway from HPV infection to development of cancer may ultimately provide more specificity in triage and diagnosis.

Biomarkers, Tumor↗

Prospective study of high grade anal squamous intraepithelial neoplasia in a cohort of homosexual men: influence of HIV infection, immunosuppression and human papillomavirus infection.

OBJECTIVE: To determine the risk of developing high grade anal squamous intraepithelial neoplasia (HG-AIN) in relation to HIV infection and immunosuppression, after controlling for the effects of human papillomavirus (HPV) infection. DESIGN: Prospective cohort study of 158 HIV-seropositive and 147 HIV-seronegative homosexual men presenting to a community-based clinic with initially negative anal cytologic and colposcopic findings. METHODS: Subjects completed self-administered questionnaires, underwent cytologic screening, and standardized unaided and colposcopic examination of the proximal anal canal for presence of abnormalities suggestive of AIN. Anal specimens were screened for HPV DNA. RESULTS: HG-AIN developed in eight (5.4%) and 24 (15.2%) HIV-seronegative and -seropositive men, respectively. Risk of HG-AIN among HIV-seronegative men was associated with detection of anal HPV types 16 or 18 by Southern transfer hybridization (STH), detection of HPV 16 or 18 at the lower levels by polymerase chain reaction but not by STH, and with number of positive HPV tests; HG-AIN risk among HIV-seropositive men was associated with detection of HPV 16 or 18 only by STH, detection of HPV types other than 16 or 18, CD4 count < or = 500 x 10(6)/l, and number of positive HPV tests. HIV-induced immunosuppression remained an independent predictor of HG-AIN after adjusting for type and level of detection of HPV; HIV infection predicted HG-AIN risk after adjustment for number of positive HPV tests. CONCLUSIONS: The association of HG-AIN with HIV, independent of HPV type, level of HPV detection and number of positive HPV tests, suggests that this increased risk cannot be entirely explained by an effect of HIV on HPV detection. Future studies focusing on factors more specific to the local microenvironment in the anal canal should help clarify these issues.

Adult↗

Every woman with an abnormal cervical smear should be referred for treatment: debate.

No dispute exists regarding the optimal management of women with moderate or severe dyskaryosis (high grade SIL). These women should have a colposcopic assessment and biopsy. Women with borderline nuclear abnormalities should have a repeat smear and undergo colposcopy only if the abnormality persists. Low-grade abnormalities (low-grade SIL) are common, and their management is relevant. We suggest that these women be referred for an immediate colposcopic assessment for the following reasons: a. a policy of cytologic surveillance allows an opportunity for default, and these women are at an increased risk of invasive cancer. b. a significant proportion of these women will have underlying CIN grade III that should be treated. c. a minority of these women revert to cytologic normality without a recurrent dyskaryotic smear and, therefore, eventually will be referred to colposcopy. d. a policy of immediate referral to colposcopy may be financially less expensive and avoid unnecessary anxiety to the woman during the period of undergoing repeated smears.

Clinical Protocols↗

In utero exposure to DES. Evaluation and followup of 199 women.

Among 199 women from 12 to 30 years of age who had been exposed to DES in utero, the colposcopic evaluation of the vagina and cervix was considered normal for only 13.6%. The incidence of colposcopically detected lesions was not related to the trimester of DES exposure, the patient's age, use of oral contraceptives, or presenting symptoms. Areas of punctation, mosaic patterns, white epithelium, and keratosis were not considered areas of adenosis. Cervical bands, hoods, cock's combs, etc., were considered as part of the cervix. Under this definition adenosis of the vagina was diagnosed in only 14.1% of the patients. Eight (4.0%) women were found to have cervical intraepithelial neoplasia (CIN), Grade 3 lesions, and an additional 36 (14.1%) women were found to have CIN, Grade 1 lesions based on the light microscopy evaluation of directed biopsies. There were no cases of clear cell adenocarcinoma. It appears that women with in utero DES exposure may be at a higher risk of developing squamous neoplasia compared with non-DES-exposed women.

Adolescent↗

Diagnostic conization of the cervix: review of 460 consecutive cases.

During a five-year period, 460 patients underwent cervical conization on the Gynecology Service at Memorial Hospital. The pertinent medical history of the 393 patients was reviewed as it related to the diagnosis of cervical intraepithelial neoplasia. All patients had repeat Papanicolaou smears and 94.4% had complete colposcopic examination using standard colposcopic procedures, endocervical curettage, and directed biopsies. For the purpose of this review, patients were separated into seven groups according to the primary and most significant indication for conization. The indications for the procedure and the histopathologic findings are discussed for each category. The usefulness of conization in the authors' institution varied according to the indication for which it was carried out. In this series of 393 patients, 18 patients (4.7%) initially diagnosed to have only intraepithelial disease, were found to have invasive carcinoma.

Adenocarcinoma↗

Impact of a colposcopy satellite clinic.

A community educational program and the introduction of a colposcope in Decatur, Alabama, led to a dramatic decrease in the relative percent of patients evaluated by conization after a positive Pap smear, and a corresponding increase in the relative percent of colposcopic evaluations. The percent of negative or dysplastic tissue diagnoses from conization was reduced from 78% before the colposcopy program to 61% after the program. It was estimated that the colposcopy program resulted in an 81% reduction in the number of conizations and that colposcopy used in lieu of conization resulted in a substantial reduction in both morbidity and cost.

Adolescent↗

Treatment of cervical dysplasia with large loop excision of the transformation zone: is endocervical curettage necessary?

Endocervical curettage (ECC) is done during most colposcopic examinations. To evaluate the need for routine ECC, we reviewed the records of all new patients seen in the colposcopy clinic at our institution from July 15, 1992, to April 15, 1993. During the study period, ECC was done in 341 patients with an adequate colposcopy. Only one case of mild dysplasia was discovered after ECC in the 123 patients referred for evaluation of cervical intraepithelial neoplasia (CIN) I or atypia seen on Pap smear. ECC specimens were positive for dysplastic cells in only 3 of 203 patients (1.4%) in whom biopsy revealed CIN I or atypia, and Pap smears for all 3 patients were suggestive of more severe lesions. Routine ECC during the initial colposcopic examination adds expense and may cause significant patient discomfort. ECC can be safely omitted in patients with CIN I on referral Pap smear and before large loop excision of the transformation zone for treatment of more severe lesions.

Adolescent↗

p53 codon 72 polymorphism and risk of intra-epithelial and invasive cervical neoplasia in Greek women.

In 1998, Storey and co-workers suggested that individuals homozygous for arginine (Arg) at codon 72 of the p53 gene are about seven times more susceptible to human papillomavirus (HPV)-related carcinogenesis than heterozygotes. Since then, several studies from Northern Europe, Japan and the USA have failed to demonstrate a similar correlation. By contrast, a study in Brazil as well as one recent study in Italian and Swedish populations showed strong positive associations. We examined the frequency of p53 codon 72 polymorphism in samples from both invasive and intra-epithelial cervical neoplasias (CIN), and compared them with samples from healthy controls. All 88 samples came from women with a Greek ethnic background. Tissue specimens were collected from archival material with histologically diagnosed low-grade CIN (LGCIN), high-grade CIN (HGCIN) or cervical cancer (CxCa). As a control, we used cellular material newly collected by cytobrush from the cervices of 30 healthy women with normal cytological and colposcopical examinations. p53 Arg homozygosity (Arg/Arg) alone was associated with four-, six- or eight-fold increased risks for LGCIN, HGCIN or invasive cancer, respectively. The frequency of the p53Arg/Arg genotype and of the proline (Pro) allele showed significant linear trends according to the degree of severity of the lesion (P = 0.0007 and P = 0.0009, respectively). Exclusion of the ten HPV16/18-negative cases did not substantially alter the Arg/Arg frequency among the groups nor the significant linear trend. Our results confirm the initial findings of Storey and co-workers, as well as the data of the Brazilian and the recent European study, but do not accord with those of the other aforementioned studies. Variations in ethnic background, laboratory performance, verification of the HPV status, definition of controls, and sample size are the most plausible explanations for this controversy. In all our samples, the distribution of the p53 alleles fits the Hardy-Weinberg equilibrium and the 0.48 frequency of the Pro allele in our controls accords well with the percentages previously reported for different ethnic groups as characteristic of the assumed north-south cline. Some authors assert that the discrepancy in the results could not be attributed to differences in the methods; however, the Brazilian study emphasized the effect of inter-laboratory variation in detecting the association between p53 polymorphism and cervical cancer. Regarding the control group, our samples were only from women with a cytologically and colposcopically benign cervical epithelium. We think that simply choosing 'normal volunteers' for collecting control DNA blood samples without knowing the status of their cervical epithelium is indeed a possible source of bias. Finally, it is very unlikely that loss of heterozygosity at the p53 locus could be a factor interfering with the allelotype distribution. Our present small study results, which suggest a biologically relevant association, provide strong evidence that homozygous arginine at codon 72 of p53 may confer a higher susceptibility to HPV-associated intra-epithelial and invasive cervical neoplasia.

Adult↗

Safety study of nonoxynol-9 as a vaginal microbicide: evidence of adverse effects.

Nonoxynol-9 (N-9) is virucidal in vitro, and is therefore a candidate microbicide for preventing sexual transmission of HIV. However, the activity of N-9 is nonspecific, suggesting that virucidal levels may produce adverse effects including epithelial disruption, inflammation of the genital mucosa, or both. A randomized placebo controlled trial of daily use of 100 mg of N-9 took place for 1 week in 40 female volunteers. Outcome measures included symptoms, colposcopic and histologic changes in the genital tract, and impact on vaginal flora. Genital irritation was reported by 10 of the N-9 and 5 of the placebo group. Colposcopy showed erythema in 9 of the N-9 group and 2 of the placebo group. Histologic inflammation was found in 7 of the N-9 group and 2 of the placebo group. Inflammatory changes were characterized by patchy infiltration of the lamina propria predominantly with CD8+ lymphocytes and macrophages, in the absence of epithelial disruption. A transient reduction in numbers of lactobacilli was observed in 9 of the 15 women using N-9, and 6 of 18 women using placebo. N-9 used for 7 days in a standard spermicidal dose was associated with increased irritation, colposcopic and histologic evidence of inflammation and was more frequently associated with reduction in numbers of lactobacilli during gel use. The clinical significance of the recruitment of cells susceptible to HIV infection to the genital mucosa is unknown but raises concerns about the suitability of N-9 as a microbicide when given in this dose.

Administration, Intravaginal↗

Home study course: Spring 2002.

OBJECTIVE: The Home Study Course is intended for the practicing colposcopist or practitioner who is seeking to develop or enhance his or her colposcopic skills. The goal of the course is to present colposcopic cases that are unusual or instructive in terms of appearance, presentation, or management or that demonstrate new and important knowledge in the area of colposcopy or pathology. Participants may benefit from reading and studying the material or from testing their knowledge by answering the questions. ACCME ACCREDITATION: The American Society for Colposcopy and Cervical Pathology (ASCCP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. The ASCCP designates this continuing medical education activity for 1 credit hour in Category I of the Physician's Recognition Award of the American Medical Association. Credit is available for those who choose to apply. The Home Study Course is planned and produced in accordance with the ACCME's Essential Areas and Elements.

Journal Article↗

Postpartum evolution of cervical squamous intraepithelial lesions with respect to the route of delivery.

OBJECTIVE.: To analyze the effect of the mode of delivery on the evolution of cervical squamous intraepithelial lesions. MATERIALS AND METHODS.: A chart review was performed of all pregnant women referred to the Northwestern Memorial Hospital Colposcopy Clinic between January 1990 and December 1998. Postpartum changes in the Pap smear and in a combined cytologic, histologic, and colposcopic impression of cervical status were evaluated. Data were analyzed using the chi, Fisher exact test, or Student t test. RESULTS.: Antepartum cytology was atypical squamous cells of undetermined significance in 23 women (7.1%), low-grade squamous intraepithelial lesions in 226 women (69.3%), and high-grade squamous intraepithelial lesions in 77 women (23.6%). Vaginal delivery occurred in 300 women (92.0%); 6 women (1.8%) had an elective cesarean section, and 20 women (6.1%) underwent a cesarean section after laboring. Of 306 women who had postpartum Pap smears, 37.9% had no change, 58.8% had improvement, and 3.3% had worsening of their cervical cytology. The rates of improvement of postpartum Pap smears were 164/285 (57.5%) following a vaginal delivery and 16/21 (76.2%) after a cesarean section (p = .81). Similarly, using a combined histologic, colposcopic, and cytologic evaluation of the cervix, the route of delivery did not affect postpartum cervical status (p = .68). CONCLUSION.: The route of delivery did not appear to influence the evolution of cervical squamous intraepithelial lesions during pregnancy and the puerperium.

Journal Article↗

Fall 2002.

OBJECTIVE: The Home Study Course is intended for the practicing colposcopist or practitioner who is seeking to develop or enhance his or her colposcopic skills. The goal of the course is to present colposcopic cases that are unusual or instructive in terms of appearance, presentation, or management or that demonstrate new and important knowledge in the area of colposcopy or pathology. Participants may benefit from reading and studying the material or from testing their knowledge by answering the questions. ACCME ACCREDITATION: The American Society for Colposcopy and Cervical Pathology (ASCCP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. The ASCCP designates this continuing medical education activity for 1 credit hour in Category I of the Physician's Recognition Award of the American Medical Association. Credit is available for those who choose to apply. The Home Study Course is planned and produced in accordance with the ACCME's Essential Areas and Elements.

Journal Article↗

Winter 2003.

OBJECTIVE: The Home Study Course is intended for the practicing colposcopist or practitioner who is seeking to develop or enhance his or her colposcopic skills. The goal of the course is to present colposcopic cases that are unusual or instructive in terms of appearance, presentation, or management or that demonstrate new and important knowledge in the area of colposcopy or pathology. Participants may benefit from reading and studying the material or from testing their knowledge by answering the questions. ACCME ACCREDITATION: The American Society for Colposcopy and Cervical Pathology (ASCCP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. The ASCCP designates this continuing medical education activity for 1 credit hour in Category I of the Physician's Recognition Award of the American Medical Association. Credit is available for those who choose to apply. The Home Study Course is planned and produced in accordance with the ACCME's Essential Areas and Elements.

Journal Article↗

Spring 2003.

OBJECTIVE: The Home Study Course is intended for the practicing colposcopist or practitioner who is seeking to develop or enhance his or her colposcopic skills. The goal of the course is to present colposcopic cases that are unusual or instructive in terms of appearance, presentation, or management or that demonstrate new and important knowledge in the area of colposcopy or pathology. Participants may benefit from reading and studying the material or from testing their knowledge by answering the questions. ACCME ACCREDITATION: The American Society for Colposcopy and Cervical Pathology (ASCCP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. The ASCCP designates this continuing medical education activity for 1 hour Category I credit of the Physician's Recognition Award of the American Medical Association. Credit is available for those who choose to apply. The Home Study Course is planned and produced in accordance with the ACCME's Essential Areas and Elements.

Journal Article↗

Detection of human cytomegalovirus DNA in 986 women studied for human papillomavirus-associated cervical neoplasia.

OBJECTIVE: The aim of this study was to assess the association of human cytomegalovirus (CMV) infection with cervical histologic findings and possible interaction with human papillomavirus (HPV) infection. MATERIALS AND METHODS: Nine hundred eighty-six women with a Pap test reported as high-grade intraepithelial lesion or with two smears reported as atypical squamous cell of undetermined significance or low grade squamous intraepithelial lesion referred for colposcopic examination were studied. All participants had a cervical Pap smear obtained and underwent colposcopically directed biopsy and endocervical curettage. Cytomegalovirus DNA and HPV DNA were detected by polymerase chain reaction (PCR) from a cervical swab. RESULTS: Human cytomegalovirus DNA was identified in 86 specimens (8.7%). Women 30 years and older had a significantly (p < .01) lower prevalence of CMV DNA (6.5%) than younger women (11.8%). Of the 86 CMV DNA-positive women, 7% had a normal histologic result, 58.1% had HPV changes (koilocytosis) in the biopsy, 11.6% had cervical intraepithelial neoplasia (CIN) 1 and 23.3% had CIN 2,3. The frequency diagnosis of koilocytosis (HPV changes) on biopsy was significantly higher in the CMV DNA-positive women (58.1%) than in the CMV negatives (29.6%). Koilocytosis on biopsy was found in 63.9% of CMV DNA-positive women who did not have concurrent HPV infection detected by PCR. Significant risk factors for koilocytosis on biopsy were CMV infection and smoking. For CIN 1, risk factors were CMV and high-risk human papillomavirus infection as well as early age of first pregnancy. The main risk factors for CIN 2,3 were HPV and CMV infections, history of smoking, and multiple pregnancies. CONCLUSIONS: The prevalence of CMV DNA is age dependent. The most frequent diagnosis on biopsy associated with CMV is koilocytosis (HPV changes), and 54% of these cases had dual HPV and CMV infection. The CMV infection appears to be associated with all histologic diagnoses, and the diagnosis of koilocytosis is not necessarily always associated with HPV infection.

Journal Article↗

Home study course: summer 2003.

OBJECTIVE: The Home Study Course is intended for the practicing colposcopist or practitioner who is seeking to develop or enhance his or her colposcopic skills. The goal of the course is to present colposcopic cases that are unusual or instructive in terms of appearance, presentation, or management or that demonstrate new and important knowledge in the area of colposcopy or pathology. Participants may benefit from reading and studying the material or from testing their knowledge by answering the questions. ACCME ACCREDITATION: The American Society for Colposcopy and Cervical Pathology (ASCCP) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. The ASCCP designates this continuing medical education activity for 1 credit hour in Category I of the Physician's Recognition Award of the American Medical Association. Credit is available for those who choose to apply. The Home Study Course is planned and produced in accordance with the ACCME's Essential Areas and Elements.

Journal Article↗

Patient acceptance of fluorescent and reflective spectroscopy as a replacement test for the pap smear.

OBJECTIVE: To determine women's acceptance of fluorescent and reflective spectroscopy (FRS) as a potential replacement test for the Pap smear. MATERIALS AND METHODS: Women scheduled for a colposcopic examination, or a colposcopic and FRS examination, completed a 22-item questionnaire that included demographic data, medical history, and preference-type questions. Data were compared using chi and Wilcoxon's rank sum tests. RESULTS: Women considered accuracy, comfort, and quick results to be the most important characteristics for new cervical cancer tests. Immediate test results were preferred strongly by both groups (control, 84.5%; scanned, 88.6%). Provided FRS was more accurate than the Pap smear, most women (control, 74.7%; scanned, 68.2%) would rather have FRS if it cost the same as a Pap smear. CONCLUSIONS: Women consider accuracy, comfort, and time critical issues with respect to FRS used as a primary screening test. Acceptance of this new technology will be facilitated by designing equipment accordingly to satisfy the concerns of women.

Journal Article↗

Women's responses to cervical interrogation by fluorescent and reflective spectroscopy.

OBJECTIVE: To determine women's responses to cervical interrogation by fluorescent and reflective spectroscopy (FRS). MATERIALS AND METHODS: A convenience sample of women scheduled for a colposcopic examination was interrogated by a cervical FRS system. Thereafter, women completed a 24-item questionnaire that assessed their responses to the spectroscopic test. Likert-scale responses were compared among subgroups using the chi test for trend. RESULTS: Most women favored FRS used for locating (97.7%; 170/174) and selectively sampling (96.6%; 168/174) cervical neoplasia. Fewer women (81.0%; 141/174) wanted FRS to replace the Pap smear. Most women were neither nervous (73.6%; 128/174) nor bothered (89.1%; 155/174) by the extra time for the FRS assessment. Women's acceptance was substantiated by 84.9% (146/174) and 90.8% (157/173) wanting their doctor to have and insurance company to pay for FRS, respectively. CONCLUSIONS: Use of FRS as a colposcopic adjunct was supported very favorably by women. Fewer women supported FRS replacing Pap smears. These high rates of approval by women should help the implementation of FRS technology.

Journal Article↗