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The ThinPrep® Processor, Model TP 2000 (Cytyc Corp, Boxborough, MA) received FDA approval in May 1996, and the AutoCyte PREP™ ®processor (TriPath Imaging Inc, Burlington, NC), received FDA approval in June 1999. Both were approved as replacements for conventional Pap smear slide preparation methods and have been specified for use in screening for atypical cells, cervical cancer or its precursor lesions, and all other cytological categories defined by The Bethesda System (TBS). Additional information is available at: http://www.fda.gov/cdrh/pdf2/P020002b.pdf. Accessed March 9, 2009.
In October 1997, the ThinPrep® 2000 System received approval for use of Preservcyt solution as an alternative collection and transport medium for gynecologic specimens tested with the Digene Hybrid Capture® System HPV DNA assay, and in May 2000 the FDA approved a second-generation model, ThinPrep® 3000, that has the capability of automatically preparing up to 80 cytology specimens. Finally, in June 2003, the FDA granted approval for the ThinPrep® Imaging System, an automated imaging and review system for assisting in primary cervical cancer screening of ThinPrep Pap Test slides.
The Digene Hybrid Capture® System (Digene Corp, Gaithersburg, MD) was approved in 1995 for use as a follow-up cervical cancer screening tool for patients with inconclusive or equivocal Pap smears. (Manos., 2001; Clavel, 1999) In March 1999, the manufacturer received marketing clearance from the FDA for its second generation, HC II HPV test, which uses Hybrid Capture II technology. The HC II HPV test, designed to qualitatively detect 18 types of human papillomavirus (HPV) DNA in cervical specimens, differentiated between two HPV groups, low-risk HPV types 6/11/42/43/44 and high/intermediate-risk HPV types 16/18/31/33/35/39/45/51/52/56/58/59/68, but could not determine the specific HPV type present. (Sarode, 2003) The following year, the FDA granted approval for removal of the reagent component "Probe A" for low-risk HPV types, permitting marketing of the device under the trade name Digene Hybrid Capture II High-Risk HPV DNA Test, for detecting only the 13 high-risk HPV types. (Cuzick, 1999) In March 2003, the FDA approved expanded use of the HC II High-Risk HPV DNA test. While this version of the test has been approved since March 2000 for women with atypical squamous cells of undetermined significance (ASC-US) papanicolaou (Pap) smear results to determine the need for referral to colposcopy, the new indication allows the test to be used in conjunction with the Pap test to screen women 30 years and older for infection with the high-risk HPV types. The information obtained from the two tests (Pap and HPV), together with the physician's assessment of cytology history, other risk factors, and professional guidelines, may be used to guide patient management. The HPV DNA test is not intended to substitute for regular Pap screening, nor is it intended to screen women less than 30 years of age who have normal Pap tests.
Although the rate of HPV infection in this group is high, most infections are short-lived and not associated with cervical cancer. (Schiffman, 2000; Clavel, 1999; Bory, 2002) To emphasize this new indication of adjunctive screening in women age 30 and older, Digene is now marketing the test under the trade name DNAwithPap™(Speculite Disposable Vaginal Light) (Trylon Associates Ltd., Harbor City, CA) received 510(k) approval on December 12, 1985. The PapSure® (Pap Plus Speculoscopy Comprehensive Pelvic Exam) (Trylon Corp., Monarch Beach, CA) received 510(k) approval on March 21,
1996. Since the summary statements have been purged from the FDA database, no further details on FDA regulations regarding this test are available. (U.S. Food and Drug Administration. Center for Devices and Radiological Health (CDRH).
K853257. Updated October 4, 2005.
On March 16, 2006 the FDA granted approval for the first optical detection system, the LUMA Cervical Imaging System Cervical Cancer Screening - Commercial Medical Management Guideline (MediSpectra, Inc.), for the use as an adjunct to colposcopy for the identification pre-cancerous and cancerous cervical lesions. In May 2005, the FDA's Obstetrics and Gynecology Devices advisory panel voted 9 to 2 to recommend that the premarket application (PMA) for LUMA not be determined approvable. However, the FDA subsequently concluded that the PMA was approvable after additional analyses of the clinical trial data provided that postmarket study be conducted to address issues concerning variation in product performance and that the indications for use be modified to stress the importance of first performing colposcopy. In addition, the FDA required the label to include a precaution advising physicians who choose to use LUMA to direct biopsy that it is unknown whether taking additional colposcopy-direct
cervical biopsies would achieve similar results. Additional information is available at:
http://www.fda.gov/cdrh/PDF4/p040028b.pdf. Accessed March 9, 2009.
Research Evidence Background Several cervical cancer screening methods are available. However the Pap smear, which may be performed alone or with
human papilloma virus (HPV) testing, is the most common method. Methods of cervical cancer screening include:
Thin-layer cytology The thin-layer, or liquid-based, cytology was developed to improve the quality and adequacy of the Pap smear. Thin-layer cytology is a variation of conventional cytology. Specimens are collected in the same fashion, but instead of smearing the sample onto slide(s), the sample is suspended in the fixative, and the specimen is sent to the cytology laboratory in solution rather than on slides, theoretically improving the probability of transferring and fixing a representative samples of cells to the slide with appropriate technique (Hayes, 2003). In addition, residual material can be used for human papilloma virus (HPV) testing, (Nuovo, 2001) which may be useful for risk stratification, especially for women with atypical glandular cells of undetermined significance (ASC-US) cytology to determine the need for colposcopy, and in primary screening of women 30 years and older when used in conjunction with liquid-based cytology (Hayes, 2003).
Computer-assisted Screening Computer-assisted screening methods were developed to improve Pap smear interpretation.Two examples are computerized rescreening utilizing neural network technology and algorithm-based rescreening. Computerized rescreening automates rescreening of Pap smears initially read as negative by a cytotechnologist. PapNet®interpret computerized images of the Pap slide identifies cells or other material on negative Pap slides that require review and creates a summary display of up to 128 images that may contain abnormalities. A cytotechnologist then reviews the summary images and can also return to the original slide using light microscopy. The PapNet system is no longer commercially available to new purchasers; however, there are new computer-assisted, interactive screening methods utilizing neural network technology currently available.
(Hayes, 2004b) Algorithm-based rescreening identifies slides that have a high probability of containing abnormal cells. For example, the AutoPap® 300 QC system, a computerized quality control system that can be used for optimizing selection of high-risk slides for rescreening, can be set for different thresholds that result in 10%, 15%, or 20% review rates. Since a classification algorithm is applied, the slides selected for review are more likely to contain abnormalities than are negative Pap slides randomly selected for review. (Hayes, 2004b) Human Papillomavirus (HPV) Testing There is clear evidence that human papillomavirus (HPV) is the primary cause of cervical cancer. Infection with high-risk HPV types is necessary but not sufficient for development of cervical cancer, and there are other cofactors and molecular events that must occur in the interim from infection to progression to cancer or its precursor lesions. HPV is transmitted sexually, with the peak prevalence occurring in women in their early to mid-20s. However, HPV infections in young women tend to be transient, while infections that persist into the 30s tend to be more long-lasting and are more likely to be high-risk types. Conversely, in the absence of infection with HPV, the likelihood of development of cervical cancer is low. (Hayes, 2004a) Cervical Cancer Screening - Commercial Medical Management Guideline Cervicography Cervicography is a technique (developed in 1981 by National Testing Laboratories) that includes visualization and photography of the cervical region for examination of atypical lesions. This is accomplished by the use of specialized equipment that combines a high-intensity strobe with a camera and macro lens, allowing high-quality colposcopic-type photographs of the cervix. When used as an adjunctive cervical screening procedure, the Pap smear is obtained prior to swabbing the cervix with an acetic acid solution in order to photograph the cervix with the Cerviscope camera. The film is then developed into a slide and evaluated by a physician.
Magnified chemiluminescent speculoscopy Magnified chemiluminescent speculoscopy is a visual examination for the screening or diagnosis of cervical cancer that uses a chemiluminescent light to aid naked-eye or minimally magnified visualization of acetowhite changes on the cervix as described below.
The LUMA Cervical Imaging system The LUMA Cervical Imaging system is an optical detection system for the screening and identification of cervical cancer.
This technique uses specialized technology to visualize the cervix as an adjunct to colposcopy. The LUMA Cervical Imaging System uses a specialized camera and light source connected to a computer to assess how different areas of the cervix respond to the light. The system uses a proprietary algorithm to process the cervical images and produce a color map of the cervix. This map indicates where the biopsy samples should be taken to maximize the likelihood of catching suspect lesions.
Most of the reviewed studies addressed three major issues in their comparison of thin-layer and conventional cytology:
specimen adequacy; detection rates of ASC-US, SILs, and carcinomas; and accuracy/diagnostic performance (sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]), using histologic data as the reference standard. Some studies also evaluated diagnostic agreement. In many instances, the investigators did not report sensitivity, specificity, PPV, and NPV, but only provided the raw data from which these values were calculated for comparison. Where histologic data was available only for a subset of the cytology cases, these calculated values were considered relative. For example, studies that did not have biopsy data for patients with negative cytology could not absolutely determine specificity.
Specimen adequacy: Of 20 studies that reported on specimen adequacy, a large majority concluded that specimen adequacy was significantly improved using thin-layer cytology. A split-sample study, using a clinically diverse population of averageand high-risk patients, reported a significant reduction in the "satisfactory but limited by" (SBLB) rate and a nonsignificant increase in the satisfactory rate (Bishop, 1998). A direct-to-vial study also reported significant reductions in the SBLB rate (35%) as well as the unsatisfactory rate (73%) (Bolick, 1998). Likewise, a retrospective cohort study, using historical conventional smear data for comparison, reported a significant increase in the satisfactory rate and decrease in unsatisfactory/SBLB rates (Weintraub, 2000). Nine additional studies reported improved specimen adequacy; 8 were directto-vial studies, (Yeoh, 1999; Baker 2002) and 1 was a split-sample study( Khalbuss, 2000). Most of these studies reported decreased SBLB rates, while some reported increased satisfactory rates and/or decreased unsatisfactory rates.
One cross-sectional study reported that 158 of 1997 liquid-based cytology tests were initially interpreted as unsatisfactory, but after reprocessing PreservCyt samples from these cases, 155 subsequently were interpreted as satisfactory. (Belinson, 2002) One split-sample study reported comparable specimen adequacy for thin-layer and conventional cytology, (Park, 2001) and another split-sample study reported that, while there were twice as many unsatisfactory thin-layer preparations and one third more with no endocervical component (ECC) present compared with conventional slides, these differences were not significant. (Bishop, 1997) In contrast, 4 studies reported poorer specimen adequacy for thin-layer cytology; 3 were split-sample studies Cervical Cancer Screening - Commercial Medical Management Guideline (Hutchinson,1999; Ferenczy,1996; Coste, 2003) and 1 was a direct-to-vial randomized controlled trial (RCT) that reported a significant increase in the SBLB and unsatisfactory rates.(Pan,2003) Detection rates: Many studies reported significantly increased detection of SILs using thin-layer cytology compared with conventional cytology (Bolick,1998; Vassilakos, 2000; Papillo, 1998; Weintraub, 2000; Baker, 2002). In addition, some studies reported significant decreases in detection of ASC-US cytology, possibly due to better preservation of abnormal cells, which allows for more definitive categorization of abnormal cells as SILs rather than classifying them in the equivocal ASC-US category. This may result in a reduction in patient anxiety and in frequency of unnecessary procedures and/or follow-up (Yeoh, 1999; Vassilakos,2002; Papillo,1998; DLA,1999). In contrast, some studies reported increases in ASC-US detection; however, this was accompanied by a reduction in the ratio of ASC-US to low-grade squamous intraepithelial lesion (LSIL). Several studies reported no difference in detection rates of abnormal cytology. (Obwegeser, 2001; Park, 2001;