Refinements and Replacements For The Conventional Pap Smear
Overview
The Pap smear has been an invaluable tool in reducing the incidence of cervical cancer over the past 50 years. Cervical cancer identified early, utilizing diagnostic methods including Pap smear, greatly improves the efficacy of treatment. Overall, the 5 year survival rate for cervical cancer detected at a localized stage is 91 percent.
Although the conventional Pap smear test helps identify cancer at an early stage, there are efforts underway to develop and market technologies that refine or potentially replace the conventional Pap smear.
Current Diagnostic Pathways
Approximately 50 million Pap smear tests are currently performed annually in the U.S., of which approximately 5 percent are determined to be pre-cancerous or cancerous. Different studies show 5 to 55 percent of Pap smear tests administered falsely produce negative results.
Approximately 50 percent of these errors are attributable to inadequacies of sample collection and approximately 50 percent of false negative errors are attributable to slide interpretation errors. In terms of collection, sampling errors result when a slide does not contain a representative sample of the cells taken from the cervix. An article in the American Journal of Clinical Pathology reported that on average, only 20 percent of a sample taken from a patient is transferred to the slide. Because the sample cells are not randomized across the collection device, the discarded portion of the sample may contain abnormal cells necessary for accurate diagnosis. Cross contamination also creates errors in diagnosis.
In terms of interpretation, under traditional Pap smear analysis a cytotechnologist analyzes the sample manually with a microscope. The cytotechnologist then classifies the sample as one of the following:
Normal (90 percent)
· Negative
Equivocal (7 percent)
· Atypical Squamous Cells of Undetermined
Significance/Atypical Glandular Cells of Undetermined Significance (ASCUS/AGUS) Patients with an equivocal result (approximately 3.5 million Pap smears annually) are either retested with conventional Pap smear, HPV DNA, or undergo colposcopy ($300 per test) and potentially biopsy ($100 per test).
Abnormal (3 percent)
· Low Grade Squamous Intraepithelial Lesions (LGSIL)
· High Grade Squamous Intraepithelial Lesions (HGSIL)
· Carcinoma
Abnormal slides are referred to senior cytotechnologist and pathologist for further review and final diagnosis. Because of the subjective nature of the test, there are errors in interpretation of the slides. With the intent to improve the quality of interpretation, CLIA regulations require that 10 percent of slides screened as negative have to be rescreened. In addition, cytotechnologists must limit screening to 100 samples per day. In spite of these efforts, there continues to be a high rate of false negative Pap smear tests.
Emerging Diagnostic Pathways
Clearly there is a cost associated with retesting patients. New technologies hope to improve the accuracy of tests for cervical cancer. Some technologies reduce errors by improving sample collection or by improving slide preparation and interpretation. Others might obviate the need for a Pap smear test entirely. Although not approved as a primary diagnostic tool currently, in the future these tools could potentially migrate from a role as follow-up/adjunct device to primary diagnostic tool. Below are descriptions of some promising products.
Liquid Cytology
Cytyc
Rather than placing the cervical sample on a slide as is performed with conventional methods, Cytyc has developed a technology, ThinPrep, which collects cervical samples with a cervix broom and suspends the sample in a preparatory solution. This technique enables more cells to be collected, rather than discarded, enabling a more representative sample collection method. In addition, the product prepares multiple slides for adjunct tests, such as HPV. ThinPrep was FDA approved in May 1996.
In terms of clinical results, the product increased detection of low-grade and more serious lesions by 65 percent in screening, 6 percent in high risk populations as compared with conventional Pap smear. False negatives were reduced from 5.6 percent with conventional Pap smear to 2.2 percent. The number of patients with subsequent benign biopsies was reduced by 31.7 percent in one study of 16,314 tests. The company is currently pursuing additional indications for the test for HPV, Chlamydia, GC (Neisseria Gonorrhea) and all STDs.
The company also manufactures the ThinPrep 2000 Processor, a sample preparation device that automates the process of preparing cervical specimens and can prepare 20 to 25 samples per hour. The ThinPrep 2000 improves the quality of slides, resulting in up to 50 percent more slides suitable for diagnostic review.
Automated Screening Devices
AutoCyte
AutoCyte offers two main products, the PREP automated liquid based sample preparation system and SCREEN image analysis system. The company also offers a Pathology Workstation product line that integrates AutoCyte's product offerings into tools for data handling of cytology and pathology images (the system offers enlarged and enhanced images for easier examination), and tools for determining prognosis of disease. The company is currently in the PMA process with the FDA.
Benefits of the AutoCyte system versus conventional Pap smear are as follows:
NeoPath
NeoPath Inc. offers AutoPap, an automated cytology screening device that uses a high speed video microscope, image interpretation software, and specially designed field-of-view computers to image, analyze and classify cells within the complex images on a Pap smear slide. The FDA approved the product in 1995 as a quality control tool to rescreen pap slides. The company has a product developed for use as a primary screener as well which FDA expected to issue a final decision in the near future.
Neuromedical Systems
Neuromedical Systems Inc. offers the PAPNET Testing System, a computerized image processing service used to detect abnormal cells on pap smears. PAPNET utilizes neural network technology to scan the 50-300,000 cells on a pap smear, pinpointing and isolating specific potentially abnormal cells. A computer video monitor displays these selected cells for focused review by a cytotechnologist. Over 130 U.S. laboratories utilize PAPNET to rescreen Pap slides.
HPV DNA Tests
Because human papillomavirus (HPV) predicts the presence and future development of cervical intraepithelial neoplasia (HPV DNA is present in more than 90% of cases of cervical cancer), there are many who suggest HPV as a less expensive and less invasive follow-up procedure in women over 30 with a conventional pap smear classification of ASCUS/AGUS or LGSIL.
Digene
Digene has developed an HPV test approved by the FDA and launched in 1997 for follow-up screening of women with equivocal pap smears. Digene markets its HPV test with Cytyc's ThinPrep system.
The company recently sponsored a joint study with Kaiser 46,000 women during under which the company's HPV HC II test identified 90 percent of women with high grade cervical disease from a population of patients with equivocal Pap smears. The study showed the referral rate for colposcopy could be reduced by 61 percent.
Oncor
Oncor has an HPV test that has yet to be approved for clinical diagnostic use. The company is currently in the PMA process.
Market Drivers
The market drivers are all the trends, issues, economic factors, and measurement trends that are pushing the market to greater growth. Market drivers for the cervical cancer diagnostics market include the following:
These technologies could reduce testing costs by improving accuracy of follow-up tests or substituting with a more accurate initial test, obviating the need for costly follow-up.
Market Restraints
The market restraints are the trends, issues, economic factors, and measurement trends that limit market growth. Market restraints are as follows:
Market Potential
With over 50 million Pap smears performed annually, these technologies will increasingly serve as an adjunct and potentially replace the conventional Pap smear.
For More information on this topic see:
Laura Wilkes' earlier articles: