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The Pap smear: a victim of its own success?

Quick, minimally invasive, and inexpensive, the Pap smear is one of the most durable innovations in the history of public health. Ironically, because of the Pap smear's outstanding success, expectations have been raised so high that any result short of perfection is likely to be viewed as malpractice.

Worldwide, cervical cancer is the third most common type of cancer in women. Since the Pap smear was introduced half a century ago, it has been responsible for a 70 percent to 80 percent decrease in death rates from cervical cancer across entire populations. (1) An estimated 12,800 women are still diagnosed each year with invasive cervical cancer, and approximately 4,600 will die of their disease. (2)

The clinical significance of the screening test described by Dr. George Nicholas Papanicolaou, one of the most effective cancer-prevention tools ever devised, went unrecognized for many years. Quick, minimally invasive, and inexpensive, the Pap smear is one of the most durable innovations in the history of public health. Ironically, because of the Pap smear's outstanding success, expectations have been raised so high that any result short of perfection is likely to be viewed as malpractice, creating the paradox of the Pap smear as a victim of its own success.

Human papilloma virus and cervical cancer

Clinical and subclinical human papilloma virus (HPV) infections are the most common sexually transmitted diseases today. Asymptomatic HPV infections can be detected in 5 percent to 40 percent of women of reproductive age. (3) It is now well established that HPV infection is the central causative factor in squamous cell carcinoma of the cervix. Risk factors for HPV include multiple sexual partners in a lifetime, sexual intercourse at an early age, early age of first pregnancy, immunodeficiency or immunosuppression, and smoking. (4)

Cervical cancer generally develops gradually and begins as a pre-cancerous condition called dysplasia. Dysplasia, depending on its severity, can resolve without treatment; often, however, it may progress to cancer. This process usually takes many years, but in rare cases, may occur very rapidly. Dysplasia is 100-percent treatable, usually without performing a hysterectomy.

Failure to obtain regular Pap smears is the single greatest risk factor for development of invasive cervical cancer. Historically, unscreened populations in the U.S. have included older women, uninsured and poor women, women residing in rural areas, and minority women (especially Hispanic and older African-American women). (2) Although recommendations for Pap smear testing vary, the American Cancer Society recommends annual Pap smears starting with the onset of sexual activity or age 18 for three consecutive normal examinations; thereafter, the interval between screenings may increase at the discretion of the physician and patient. (5)

Pap smear technology

The primary purpose of the Pap smear is to identify patients who have cellular changes that place them at risk for the development of cervical cancer. The Pap smear is most effective in detection of abnormalities in squamous cells. While other types of cancer, such as that of the endocervix and endometrium, can be detected by Pap smear, the sensitivity and specificity for detection of these cancers are far lower than for squamous cell carcinoma, the most common type of cervical cancer.

The Pap smear is a simple-appearing, but relatively complex, test that requires careful patient preparation, skill in specimen collection, skilled laboratory processing, and professional interpretation. The conventional Pap smear is performed by obtaining cells from the cervix with a soft brush and rubbing them onto a glass slide, followed by immediate fixation. The slides are then stained with the Papanicolaou stain and reviewed by a cytotechnologist.

Currently, laboratories are increasingly using thin-layer technology (ThinPrep Pap Test by Cytyc Corp.). This method consists of collecting cells with a soft brush, rinsing the specimen into a special fluid preservative, and making a thin-layer slide using an automated slide processor. The slide is stained with the conventional Pap stain. This method provides better quality preparations with better cell preservation, fewer inadequate samples, elimination of obscuring factors such as inflammatory cells and blood, and homogeneity of the sample. An additional advantage is that the remaining material can be used for HPV DNA testing. (6) Thin-layer technology has been shown to increase the detection of cell abnormalities when compared with conventional Pap smears.

Computer-assisted, automatic scanning devices are used primarily for re-screening Pap smears for quality control and are not yet FDA-approved for primary screening. While these instruments may benefit laboratories through reduction of false-negative rates, increased sensitivity, and increased throughput, they are also expensive. (2)

HPV DNA testing can be achieved by the polymerase chain reaction (PCR) or by hybrid capture systems. (6) While the PCR method can detect low concentrations of HPV DNA, this can also lead to a high number of false-positive results, which may result in further work-up, expense, and anxiety for the patient.

Each year, approximately 50 million women undergo Pap testing, and of these, 7 percent (3.5 million) are diagnosed with a cytological abnormality requiring additional follow-up or evaluation. (7)

The art of cytology

Equal parts art and science, cytotechnology is labor-intensive, complex, and poorly understood by most people, including medical personnel. Pap smear diagnosis is both difficult and subjective, depending entirely on human judgment.

The complexity of Pap smear interpretation is due to many factors, including the variability of the mixed cell population on the slide and the wide range of inflammatory and reparative processes occurring in the cervix. In addition, the cytologist must also take into account cyclic hormonal changes, pregnancy-induced alterations, and postmenopausal changes that may affect cell morphology. Because cells have only a limited repertoire of responses to injury, complex mimicry between benign and malignant processes can lead to considerable diagnostic difficulty.

The average Pap smear contains anywhere from 50,000 to 300,000 cells and may have up to a half-million cells for analysis. (8) Pap smear screening has been compared to reading 50 to 80 manuscripts in a day--each containing between 50,000 to 500,000 words--in search of errors. (4) Not surprisingly, when abnormal cells are sparse, they are more difficult to detect, like the proverbial needle in a haystack. In one study, the odds of a false-negative report were 23.7 more times more likely in slides with fewer than 50 abnormal cells compared with those with 200 or more abnormal cells. (9)

An unfortunate paradox of the Pap smear is that serious, high-grade lesions may be more difficult to detect than low-grade lesions because they tend to exfoliate fewer cells. These high-grade, abnormal cells are often very small and sometimes have more subtle morphologic abnormalities, making them more difficult to identify. (8) Compounding these difficulties, high-grade lesions may be hidden in the endocervical canal, where they are more difficult to sample.

Screening vs. diagnostic testing

The Pap smear is a screening test, not a diagnostic test. Screening tests, by definition, will have a certain percentage of false positives and false negatives; however, screening tests are designed to have a low false-negative rate at the expense of increased false positives. Even in the best cytology laboratories, false-negative rates are around 5 percent, but may be as high as 20 percent. (10, 11) For a woman with an average risk of HPV, there is only about 1 chance in 1,000 that her negative Pap smear has been misread. (4,8) The Pap smear is often misunderstood by both lay people and medical personnel who do not understand the concept that the Pap smear is an excellent screening test, not a poor diagnostic test.

Both false-positive and false-negative results have consequences. False-positive reports prompt an expensive evaluation, along with patient anxiety. False-positive rates are around 4 percent, similar to false-negative rates. (12)

A false-negative report is even more dangerous, since a delayed or missed diagnosis may result in patient injury or death. Reasons for false-negative results are numerous and include sampling errors (failure to have obtain abnormal cells on the slide), screening errors (failure to find abnormal cells on the slide), diagnostic errors (failure to properly interpret abnormal cells), and miscellaneous laboratory errors related to staining problems, mislabeling, etc. (8) Other factors contributing to the false-negative rate are the presence of few abnormal cells, small cells, cytologically bland cells, and obscuring processes, such as inflammation or blood. (8) False-negative results have important medical, financial, and legal implications, and in the U.S., they are a leading cause of malpractice litigation. (3)

Abnormal Pap smears are generally followed by colposcopically directed biopsy, which is considered the diagnostic gold standard. Because of the Pap smear's remarkable success, a subtle shift has occurred from Papanicolaou's vision of an inexpensive, widely accessible screening test toward a greater emphasis on its diagnostic accuracy.

Quality assurance issues

Before 1988, under CLIA '67, laboratories were required to do 10 percent random rescreening of negative Pap smears. Under CLIA '88, the 10 percent random rescreening is no longer mandated, but laboratories must perform rescreening of a mixture of both random cases and high-risk cases. (11) Quality assurance mechanisms may include random rescreening, targeted rescreening of high-risk patients, retrospective rescreening in patients with newly diagnosed disease, computer-assisted rescreening, and cytologic-histologic correlation. (9) Cytologic-histologic correlation is difficult in settings such as small hospitals, in which the Pap smears are interpreted at an outside reference laboratory, while the biopsies are interpreted by the hospital's pathologists.

The Pap smear under siege

Because of increased awareness and focus on the limitations of Pap smears, we are now seeing a litigation explosion which has surged since 1992. (1) Both cytotechnologists and pathologists may find themselves named as defendants in malpractice lawsuits. Pathology, once one of the lowest-risk specialties for malpractice insurers, has become one of the highest-risk specialties, primarily because of Pap smear litigation. Currently, 10 percent of malpractice lawsuits against pathologists involve misread Pap smears. (13) In one study, the dollar amounts assigned to these cytology claims totaled 25 percent of all pathology malpractice claims, so that cytology claims appeared on the average to be more expensive than noncytology pathology claims. (14)

There are several highly publicized cases of litigation involving Pap smears. Many people trace the current Pap smear crisis to an expose of high false-negative Pap smear rates by the Wall Street Journal in late 1987. (15,16) This series of articles led to Congressional hearings and two conferences sponsored by the Centers for Disease Control. Plans were already underway to revise CLIA '67, and because of this adverse publicity, the public and Congress were anxious to enact some cytology regulations quickly. Revisions to CLIA '67 were incorporated into CLIA '88. CLIA '88 was passed and subsequently implemented in 1992, except for cytology proficiency testing, which has remained an insurmountable logistic problem. (15,16)

A highly publicized case in 1993 involved Newport Hospital in Newport, RI. In this case, a woman died of invasive cervical cancer after having four consecutive Pap smears misread as normal or near normal over a seven-year period, when in fact they showed evidence of high-grade dysplasia or outright carcinoma. (17) The Pap smear re-screening process instituted in the hospital following the case and the associated expenses cost almost $1 million. No third-party payers covered this expense, so the entire amount was paid from hospital funds. (17)

In 1995, criminal charges were brought against Chem-Bio Corporation in Milwaukee, WI. The laboratory was charged with homicide by reckless conduct for the alleged misreading of Pap smears of two women. The laboratory eventually pleaded no contest and paid a fine of $20,000. (18)

In 1995, Chicago Insurance Company, a long-term underwriter of malpractice insurance for cytotechnologists, pulled out of the cytotechnology market, saying that covered cytotechnologists were the source of "horrendous losses." (19) More recently, the American Society for Cytotechnology has been unable for several years to find any U.S. insurance company willing to underwrite group liability coverage for independent contractor cytotechnologists. (20)

It is thought that less than 3 percent of preventable cervical cancers can be traced to misread Pap smears. (8) Ironically, the single most important error is failure of women to have a Pap smear in the first place; between 60 percent to 90 percent of cervical cancer cases are due to infrequent Pap smear screening. (8)

The Pap smear is not a perfect test, and yet cytologists and cytopathologists are being held to an impossible standard of perfection in malpractice litigation. (8) This zero-error standard is both unreasonable and impossible to achieve.

Costs

Increased costs associated with litigation will ultimately be borne by the consumer and will result in increased overall Pap smear screening costs. Added to the additional costs of thin-layer preparation, computer re-screening, compliance with government regulations, and malpractice insurance, some people suggest that a $100 Pap smear may soon become a reality. (21)

The U.S. government has estimated that proficiency testing of cytotechnologists and pathologists costs between $153 million and $524 million per year. (10) Although this is a relatively small cost spread over all laboratories, it is not insignificant for an economically marginal test or a loss leader, as Pap smears are sometimes regarded in large laboratories. (10)

Some researchers have suggested that it is more cost effective to increase the frequency of Pap smear testing while keeping prices low, rather than to lower the false-negative rate and significantly raise the price of the Pap smear. (21,22) All additional efforts to prevent errors will add costs. Healthcare payers, and even patients themselves, are unlikely to be prepared to increase their payments for Pap smears. (22)

The future of the Pap smear

Because of today's current legal climate, every decision made in the cytopathology laboratory is done with the omnipresent threat of a malpractice suit.

The economic and social consequences of error to the family and reputation of the cytologist loom like the sword of Damocles. The current legal climate threatens recruitment and retention of talented cytology professionals.

The liability issue threatens women and public health; the public does not understand that continued availability and affordability are threatened by this litigation. (22) Loss of the Pap smear as an affordable, widely available test would likely lead to increased cervical cancer rates. (8,23) Successful defense of Pap smear lawsuits is important if the public is not to lose faith in a valuable screening test that has been critical to women's health. (18)

Well-intentioned efforts to improve the Pap smear may have the unintended and paradoxical effect of increasing the number of cervical cancers by raising costs and decreasing access to this test. (8) We need to keep in mind that virtually everything done to "improve" the Pap smear takes time and costs money. (8) Because most technologies will add to the cost of Pap smears, society must judge the value of these added costs compared to the benefits to women's health. These decisions cannot be made by cytopathology professionals alone.

Cost-effectiveness studies on Pap smears have focused exclusively on healthcare system costs and perspectives and have not reflected the broader societal, personal or familial costs of undetected cervical cancer, thus reflecting the biases of healthcare payers and failing to take into account consumer preferences. (5)

The unrealistic expectations of an error-free Pap smears help fuel the current medicolegal crisis and are partly based in ignorance. (23) A negative Pap smear is not a guarantee that a woman does not have cancer. Women need to know that successful cervical cancer screening is based on repeated examinations at appropriate intervals; both the patient and her physician bear some responsibility for this portion of the Pap smear procedure. (23)

The most successful cancer-screening test in medical history, the Pap smear is at a crossroads. The Pap smear is no longer judged by its success, but rather by its limitations. (21) Women, physicians, insurance carriers, managed care administrators, health advocacy groups, and legislators need to be educated about cervical cancer screening. Problems surrounding the Pap smear are a societal problem, and significant changes may not occur until society becomes convinced that there is a threat to access for affordable cervical cancer screening.

References

(1.) Austin RM. College of American Pathologists Conference XXX on quality and liability issues with the Papanicolaou smear: Introduction. Arch Pathol Lab Med 1997; 121:227-228.

(2.) American Society of Cytopathology. Cervical cytology practice guideline. Diagn Cytopathol 2001; 25:3-24.

(3.) Franco EL, Duarte-Franco E, Ferenczy A. Cervical cancer: Epidemiology, prevention and the role of human papillomavirus infection. Can Med Assoc J 2001; 164:1017-1025.

(4.) Rinas AC. The gynecological Pap test. Clin Lab Sci 1999; 12:239-245.

(5.) Colgan TJ. Austin RMA, Davey DD. The Annual Papanicolaou test. Women's safety and public policy. Cancer Cytopathol 2001; 93:81-85.

(6.) Michalas SP. The Pap test: George N. Papanicolaou (1883-1962). A screening test for the prevention of cancer of uterine cervix. Eur J Obstet Gynecol Reproduct Biol 2000; 135-138.

(7.) Wright TC, Cox JT, Massad LS, et al. 2001 Consensus guidelines for tha management of women with cervical cytological abnormalities. JAMA 2002; 287:2120-2129.

(8.) DeMay RM. Common problems in Papanicolaou smear interpretation. Arch Pathol Lab Med 1997; 121:229-238.

(9.) Davey DD. Quality and liability issues with the Papanicolaou smear. The problem of definition of errors and false-negative smears. Arch Pathol Lab Med 1997; 121:267-269.

(10.) Frable WJ. Does a zero error standard exist for the Papanicolaou smear? A pathologist's perspective. Arch Pathol Lab Med 1997; 121:301-272.

(11.) Naryshkin S. The false-negative fraction for Papanicolaou smears. How often are "abnormal" smears not detected by a "standard" screening cytologist? Arch Pathol Lab Med 1997; 121:270-272.

(12.) Colgan TJ, Davey DD. Q&A. CAP Today, May 1999; p.91.

(13.) Greer BE. The gynecologist's perspective of liability and quality issues with the Papanicolaou smear. Arch Parhol Lab Med 1997; 121:246-249.

(14.) Scott MD. Liability issues with the Papanicolaou smear. An insurance industry perspective. Arch Pathol Lab Med 1997; 121:239-249.

(15.) Davey DD. Papanicolaou smear 5-year retrospective review. What is required by the Clinical Laboratory Improvement Amendments of 1988? Arch Pathol Lab Med 1997; 121:296-298.

(16.) Frable WJ. "Litigation cells" in the Papanicolaou smear. Extramural review of smears by "experts." Arch Pathol Lab Med 1997; 121:293-295.

(17.) Sampson AJ. Liability issues with the Papanicolaou smear. The view of a hospital administrator at Newport Hospital, Newport, Rhode Island. Arch Pathol Lab Med 1997; 121:241-249.

(18.) Varner CD. Liability issues with the Papanicolaou smear. A defense lawyer's perspective. Arch Pathol Lab Med 1997; 121:315-320.

(19.) Austin RM. Experts fuel Pap liability woes. CAP Today, July 1994, pp. 9, 12-13.

(20.) Austin RM. Letter to the editor. CAP Today. August 2801, pp. 6, 11.

(21.) Austin RM. College of American Pathologists Conference XXX on quality and liability issues with the Papanicolaou smear: Summation. Arch Pathol Lab Med 1997; 121:341-342.

(22.) Derman H. Duality and liability issues with the Papanicolaou smear. Lessons from the science of error prevention. Arch Pathol Lab Med 1997: 121:287-291.

(23.) Stanley WM. Quality and liability issues with the Papanicolaou smear: The role of professional organizations in reform initiatives. Arch Pathol Lab Med 1997; 121:321-325.

RELATED ARTICLE: Dr. George N. Papanicolaou: Pioneer of cytology

George N. Papanicolaou was born May 13, 1883, in Greece, on the island called Euboea. He was described as a sensitive, highly literate, and sentimental child. In high school, he studied languages, classical philosophy, literature, and music. Encouraged by his father to carry on his family practice, he obtained his M.D. degree at age 21 in 1804 from the University of Athens.

In his post-doctoral work, Dr. Papanicolaou hypothesized that cells could be affected by the hormonal environment in which they exist. He initially examined cells at various points of the estrus cycle in rodents. Seeing that these cells differed in their appearance at various stages of the estrus cycle, he then hypothesized that human beings may well show similar changes.

In 1925, he examined a smear of a female patient known to have cancer of the uterus. The exfoliated cells that he saw were described by others as "his most thrilling discovery." After reviewing many more cases, in 1928, he published his legendary article, titled "New Cancer Diagnosis." The article was met with considerable skepticism by the established medical community, not an uncommon phenomenon in academic disciplines. With the passage of time, however, his discovery has proven to be one of the most effective, efficient, inexpensive, and readily accessible medical tests, reducing the incidence of death from cervical carcinoma approximately tenfold.

In addition to his work with the female reproductive system, he also examined urine specimens and established extensive morphologic drawings of the cells seen in his work, each representing progressive degrees of cytologic malignancy as seen under the microscope.

In 1951, Dr. Papanicolaou assumed the directorship of the Papanicolaou Cancer Research Institute in Miami, named in his honor, but he died only a few months later. He did not live to accomplish his dream of creating an Institute of Cytology in his homeland, where he had planned to spend the last years of his life. In 1995, the government of Greece issued a 10,000 drachma banknote in his honor. He was also honored by three different nations by having his face placed on postage stamps. In 1978, then-First Lady Rosalyn Carter presented a postage stamp issued in the U.S. to Mrs. Papanicolaou at the White House.

Dr. Carmen Steigman is a member of the Department of Pathology at Garden City Hospital in Garden City, MI. Dr. John Vernick and Dr. Peisha Yan are both members of the Pathology/Cytopathology Division at Hutzel Hospital, Detroit Medical Center. at Wayne State University. Detroit, MI.
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Author:Steigman, Carmen K.; Vernick, John P.
Publication:Medical Laboratory Observer
Geographic Code:1USA
Date:Aug 1, 2002
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Previous Article:Refresher courses available for medical technologists. (Letters to the Editor).
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