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Detecting cancer outcomes in the U.S. population following major changes in health behaviors often takes decades, as opposed to years. This is because many cancers are slow growing and don’t manifest themselves in a detectable way until years after the event or events that may initiate them. This delay in changing rates is particularly true for mortality outcomes in women for two cancers—lung and breast—affected by significant changes in health behaviors in the past 10 to 20 years.

Shifts in smoking patterns, both initiation and cessation, are fairly easy to track, and have been linked to a number of seminal events. Men started smoking at increasing rates during World War II and didn’t begin noticeable cessation efforts until after the U.S. Surgeon General’s announcement linking smoking to lung cancer in the 1960s. Even then, it took almost four decades to see a drop in death due to lung cancer for men, and indeed, it was not until the end of the 20th century that such drops were noticeable by statisticians. By contrast, women didn’t take up smoking as much as men until the 1960s, when cigarette manufacturers started designing and heavily promoting products for women. In part because they began smoking in large numbers later in the 20^th century, cessation of smoking by women occurred years after men began to quit.

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With the release of 2009 data from NCI’s SEER program on April 16, 2012, experts can now point to a statistically significant decline in lung cancer mortality for women. This turning point is particularly important, as lung cancer is the No. 1 cancer killer for both men and women. Lung cancer cases make up nearly a quarter of all cancers deaths in the U.S.  A continuation of the trends showing a drop in lung cancer mortality for both sexes would indeed be good news for the health of the nation.

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The other cancer in women that has been noticeably affected by a change in health behaviors this century is breast cancer. When NIH released the first results from the Women’s Health Initiative in 2002, the study pointed to an increased risk for breast cancer among women who used hormone replacement therapy. That news caused many women to stop taking hormone replacement drugs, and in 2003 the SEER program reported a marked decrease in breast cancer incidence.  Now, almost 10 years later, the SEER data for 2009 show no appreciable change in incidence of breast cancer since 2003.  Whether the decline in HRT use has affected breast cancer mortality rates is still unclear, in part, due to high survival rates experienced by many breast cancer patients.

In the accompanying video interview, Kathy Cronin, Ph.D., acting chief of NCI’s Surveillance Research Program, discusses lung and breast cancer results from the SEER 2009 release, as well as other outcomes reported in this year’s release.

For more information on using the data released as part of SEER’s annual Cancer Statistics Review, see our article from last year’s release:  Need stats? How to find the most up-to-date cancer statistics

Click here to view the embedded video.

Click here to view the embedded video.

HPV can infect normal epithelial cells. The human papilloma virus is housed in a protective shell made of a protein called L1. As the virus enters a cell, the L1 protein coat degrades, leading to the release of the virus’ genetic material in a cell’s nucleus. In the nucleus, the DNA from the virus is transcribed by messenger RNA, which carries viral DNA snippets to the cellular DNA, where it is integrated and eventually translated into proteins called E6 and E7, which can lead to cancer.

How immune cells are activated to attack foreign invaders

While vaccines to prevent infectious diseases such as measles, mumps, and polio have been available for decades, prevention vaccines for cancer have been much slower to reach the commercial market. To date, the only cancer vaccine licensed by the Food and Drug Administration is a prophylactic vaccine against hepatitis B virus, an infectious agent associated with liver cancer.

However, it seems very likely that a second prophylactic vaccine will reach the market in the next few years. The promising contender is a vaccine against human papillomavirus (HPV), the primary cause of cervical cancer. Early results from a trial conducted by Merck & Co., Inc. in 1,500 young women showed that the vaccine was 100 percent effective in preventing persistent HPV infection and low-grade cervical cytological abnormalities attributable to a strain of the virus known as HPV-16. (N Engl J Med 2002;347:1645). This type of HPV accounts for about half of the cervical cancer cases world-wide. (For more information on HPV types, see BenchMarks April 2002.)

Douglas Lowy, M.D., a National Cancer Institute (NCI) scientist since 1975, has conducted research on the molecular biology and growth regulation of tumor viruses as well as early phase human trials of a vaccine against HPV-16 (J Natl Cancer Inst 2001;93:284). He and his NCI colleagues developed the technology that underlies the candidate prophylactic HPV vaccine. He is chief of the Basic Research Laboratory and the Laboratory of Cellular Oncology at the Center for Cancer Research, where he also serves as deputy director. He was interviewed by Nancy Nelson.

It seems as though the HPV vaccine would be most useful in developing countries, not only because 80 percent of the cases of cervical cancer occur in those countries, but because of the high cost of Pap smear screening and follow-up. Is that true? (In the United States, these costs are estimated to be $5 billion every year.)

Dr. Lowy: It depends. We have enough money for routine Pap smears. If everyone had routine Pap smears, we could prevent almost all cervical cancers today. However, the developing world doesn’t have the same financial resources, and the preponderance of cervical cancers occur in the developing world. There is really no alternative in the developing world, so the opportunity to save lives and reduce the incidence of cervical cancer is greater there.

Having said that, the vaccine could have a tremendous impact on women in the developed world. In the short term, it would reduce the incidence of serious abnormal Pap smears. There’s a lot of anxiety as well as morbidity that goes with those. It would also reduce the number of follow-ups needed for abnormal Pap smears and the number of surgeries needed for high-grade dysplasia.

One of the ironies is that the impact of the vaccine will be felt sooner in the developed countries than in the developing world. That’s because changes in the cervix occur relatively soon after infection. Let’s say that today you could implement world-wide vaccination. What would happen five years from now? In the developed world, there would be a reduction in abnormal Pap smears and a reduction in need for surgeries to treat high-grade dysplasia. In the developing world, the impact will be zero. That’s because cervical cancers don’t occur until 15 to 25 years
after you get infected. So actually, you will see no benefit until you get out to that time. It’s one of the “deficiencies” of a purely preventive vaccine.

One more point is that you won’t be able to eliminate cervical cancer screening because the vaccine will only target a subset of the viruses that are implicated in cervical cancer.

Is HPV infection required for cervical cancer to develop?

Dr. Lowy: Yes. If you don’t have HPV infection, you don’t get cervical cancer. The latest study, published about three years ago, showed that over 99.5 percent of cervical cancers contained HPV. Because the types of HPV linked to cervical cancer are sexually transmitted, behaviors such as beginning sexual intercourse at an early age (especially age 16 or younger) and having many sexual partners increase the chance that a woman will develop an HPV infection in the cervix.

Is HPV infection alone enough to cause cervical cancer?

Dr. Lowy: Most people don’t develop cervical cancer after infection. Even an infection with high risk HPV-16 is usually a self-limiting infection. You get it and it goes away. Probably at least 80 percent of HPV-16 infections end up going away — maybe 90 percent. Somewhere between 10 to 20 percent of HPV-16 infections will be associated with some cytological abnormality. A smaller proportion will persist and go on to become cervical cancer.

Besides exposure to HPV, what are other risk factors for cervical cancer?

Dr. Lowy: The biggest clearly identified risk factor is immuno-suppression. Survivors of renal transplant, AIDS patients, and people with impaired cell-mediated immunity are at high risk of persistent HPV infection, high-grade dysplasia, and cervical cancer. Beyond that, there is epidemiologic evidence implicating smoking. It makes some sense because there are carcinogens in cigarette smoke that can be found in the vaginal tract.

You published a paper in February 2001 in the Journal of the National Cancer Institute showing proof-of-principle for your HPV vaccine. Could you briefly describe how the vaccine was made and the results?

Dr. Lowy: The vaccine we used consists of several copies of an HPV-16 protein, L1. By way of some background, our breakthrough
observation in 1992 (Proc Natl Acad. Sci USA 1992;89:12180-12184) showed that multiple copies of the L1 protein alone can join together to form a 3- dimensional structure that resembles the virus – it has the shell of the virus but without the viral genetic information inside. When assembled, the L1 proteins are called virus-like particles, or VLPs. Besides this ability to self-assemble, our further work showed that vaccinating animals with the VLPs of animal papillomaviruses protected them from subsequent viral challenge (J Virol 1995;69:3959-3963 and Virology 1996;219:37-44). All of this earlier work led us to believe that the L1 protein of HPV-16 would be a good candidate for a human vaccine.

Using insect cells, we made a relatively pure preparation of VLPs that we used to immunize normal volunteers, looking for safety and immunogenicity.

There were four bottom line results. The vaccine was very well tolerated. There were almost no side effects due to the vaccine itself. The second point was that everybody sero-converted and developed high levels of neutralizing antibodies. No one was resistant. The third finding was that at the high dose, you didn’t need adjuvant. The last point is that the levels of antibody that people developed were similar to levels that protected animals against infection with animal papillomavirus. So, while you couldn’t say the level of antibodies in humans was protective,
you could say that people behaved the same way as rabbits and mice, in terms of making robust immunological responses.

Are you continuing to use the vaccine in future trials?

Dr. Lowy: We’ve tested the vaccine in a larger group of women to confirm the results. In phase II trials involving about 100 women, we found that the vaccine induces a durable antibody response. When we measured the antibody level six months after the last vaccination, there was a three-fold drop in level compared to one month after the last vaccination, and that’s considered a small drop in level. So, the response is durable.

The other thing we did was to measure antibody at the cervix. We found antibody at the cervix. There is one wrinkle, however. The level of the antibody is different for women who are on oral contraceptives compared with those who are menstruating. For women on contraceptives, the levels are constant, whereas for menstruating women, the antibody levels vary by a factor of 10, depending on where you are in your ovulatory cycle. Whether this has any implications for protection, we don’t know, but we’re going to look into it.

What other HPV vaccine trials are taking place?

Dr. Lowy: Merck has embarked on a large phase III trial with a vaccine against HPV types 16, 18, 6, 11. (Types 6 and 11 cause genital warts.) Tens of thousands of women in the United States, Latin America, Europe, Asia, and Australia are involved. GlaxoSmithKline is testing a vaccine against types 16 and 18.

The question now is, can you make a commercial vaccine that has multiple components that will be highly protective. Merck already has immunological data that they reported in October at the HPV international conference. They found that the immunological response to HPV-16 in the four-component vaccine is as good as the response to HPV-16 alone. In other words, there’s no suggestion of attenuation of the response as a consequence of giving multiple HPV types.

It seems like everything looks extremely hopeful for these vaccine trials. Dogs, rabbits, and calves were protected against papillomavirus infection with similar vaccines, and the early results from human trials seem to be very favorable. Is there any reason to believe that things won’t go fabulously well?

Dr. Lowy: It’s as good as you could hope for. It’s an immunogen that people see normally. You’re just giving them more of it. On the other hand, it’s possible that out of 20,000 people, two might have a terrible side effect. We certainly hope that’s not true, but we really don’t know that now, because the vaccine hasn’t been given to 20,000 people. However, barring that, it’s hard to imagine that if there’s as much protection as you see in the Merck trial, that you won’t also get protection with a multivalent vaccine. At this point, if you didn’t see protection, you might say, “Well, somebody made the vaccine wrong.”

Is immunizing men just as important as immunizing women?

Dr. Lowy: It is assumed in the developed world that it will be recommended that men be immunized, but it is not such a straight forward issue. There are several points. The first is that at the moment there is no evidence that immunizing men is beneficial. It might be useful to do studies that indeed show that the vaccine would have some protection — not so much to protect men against HPV-16, but to have a rationale for immunizing men as a way to protect women.

The second issue is that the more protective the vaccine is for women, the better off you would be in immunizing all women, rather than immunizing two-thirds of men and two-thirds of women. You would get more protection if you immunize 100 percent of women, rather than immunizing two-thirds men or two-thirds women. To make the vaccine more relevant to men, Merck is incorporating HPV-6 and HPV-11, which are the main causes of genital warts, which are as big a problem for men as women. If there is a reduction in infection with those HPV types, then men would get a direct benefit.

But, on a population-wide basis and from a public health point-of-view, the most important thing is to immunize women. If you have enough money, you may want to immunize both men and women. But the rationale for immunizing men is not as strong as women.

Animation/Video

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Text Transcript

The Immune System and Cancer Vaccines: Cancer vaccines, whether to prevent or treat cancers, take advantage of the immune system’s ready-made network of cells and organs that work together to defend the body against attack by “foreign” invaders. When a foreign organism or entity (an antigen) enters the body, a variety of immune cells and molecules mount an appropriate response. Lymphocytes are one of the main types of immune cells. The most common lymphocytes, B cells and T cells, patrol the blood and lymph system for foreign antigens. Cancer vaccines currently under development are designed to stimulate primarily B or T cells to mount an attack against foreign entities.

The job of the B cell is to ambush antigens circulating in the bloodstream. Protruding from its surface are antibody molecules poised to bind foreign agents such as toxins, bacteria or viruses. Only specific antigens will bind to each B cell.

Once the triggering antigen binds, the B cell digests it, and displays antigen fragments with the help of a marker molecule on the cell surface.

The antigen/marker combination is recognized by a T cell, which in response secretes lymphokines.

These, in turn, stimulate the multiplication and maturation of B cells into plasma cells. The plasma cells pour millions of identical antibody molecules into the bloodstream.

These antibody molecules ambush and inactivate the matching antigens in the blood.

While B cells attack soluble antigens in the body’s fluids, the job of the T cells is to attack cells that have either been infected by viruses or altered by cancer.

Cells that display pieces of foreign antigens on their surface with the MHC molecule are called antigen presenting cells (APC). APCs are either B cells, macrophages or dendritic cells. T cells recognize antigens only when they are bound to cell-membrane proteins called major histo-compatibility complex (MHC) molecules. Cells that display pieces of foreign antigens on their surface with the MPH molecule are called antigen presenting cells (APC). APCs are either B cells, macrophages or dendritic cells. T cells recognize antigens only when they are bound to cell-membrane proteins called major histo-compatibility complex (MHC) molecules.

When a T cell is activated by binding to the antigen/MHC complex, it secretes lymphokines. The secreted lymphokines cause several reactions.

Some Lymphokines spur the growth of Memory T cells. Memory T cells are primed to fend off additional attacks by the same antigen. These have a longer lifespan in the body and respond more readily to a second antigen assault than the original T cell. Some T cells become natural killer T cells, known as cytotoxic T cells (or CTL), which attack infected or abnormal cells directly.

Some T cells become natural killer T cells, known as cytotoxic T cells (or CTL), and attack infected or abnormal cells directly. The lymphokines also attract other immune cells, such as macrophages and neutrophils, to the site of the foreign invasion.

Treatment Vaccines: The strategy that researchers use for treatment vaccines involves injecting cancer-specific antigens into patients. The hope is that these antigens will stimulate B and T cells in the immune system to attack cancer cells without harming normal cells.

Prevention Vaccines: Prevention vaccines, on the other hand, are given to healthy individuals to stimulate the immune system to attack cancer-causing viruses and prevent viral infection. Non-infectious viral proteins from cancer-causing viruses are commonly used as antigens to stimulate the immune system for prevention vaccines. This is the same strategy used for vaccines for polio or measles.

Audio Clips

1. Douglas Lowy, M.D., discusses pap smears and worldwide cervical cancer prevalence.

      ( Audio – Length: 00:48 )

   Text Transcript

   Douglas Lowy, M.D., discusses pap smears and worldwide cervical cancer prevalence.

   If everyone had routine Pap smears, we could prevent almost all cervical cancers today. However, the developing world doesn’t have the same financial resources, and the preponderance of cervical cancers occur in the developing world. There is really no alternative in the developing world, so the opportunity to save lives and reduce the incidence of cervical cancer is greater there.

2. Douglas Lowy, M.D., discusses cervical cancer vaccine effectiveness.

      ( Audio – Length: 02:08 )

   Text Transcript

   Douglas Lowy, M.D., discusses cervical cancer vaccine effectiveness.

   Having said that, the vaccine could have a tremendous impact on women in the developed world. In the short term, it would reduce the incidence of serious abnormal Pap smears. There’s a lot of anxiety as well as morbidity that goes with those. It would also reduce the number of follow-ups needed for abnormal Pap smears and the number of surgeries needed for high-grade dysplasia.

   One of the ironies is that the impact of the vaccine will be felt sooner in the developed countries than in the developing world. That’s because changes in the cervix occur relatively soon after infection. Let’s say that today you could implement world-wide vaccination. What would happen five years from now? In the developed world, there would be a reduction in abnormal Pap smears and a reduction in need for surgeries to treat high-grade dysplasia. In the developing world, the impact will be zero. That’s because cervical cancers don’t occur until 15 to 25 years after you get infected. So actually, you will see no benefit until you get out to that time. It’s one of the “deficiencies” of a purely preventive vaccine.

   One more point is that you won’t be able to eliminate cervical cancer screening because the vaccine will only target a subset of the viruses that are implicated in cervical cancer.

3. Douglas Lowy, M.D., discusses developing an HPV vaccine for men.

      ( Audio – Length: 01:30 )

   Text Transcript

   Douglas Lowy, M.D., discusses developing an HPV vaccine for men.

   It is assumed in the developed world that it will be recommended that men be immunized, but it is not such a straight forward issue. There are several points. The first is that at the moment there is no evidence that immunizing men is beneficial. It might be useful to do studies that indeed show that the vaccine would have some protection — not so much to protect men against HPV-16, but to have a rationale for immunizing men as a way to protect women.

   The second issue is that the more protective the vaccine is for women, the better off you would be in immunizing all women, rather than immunizing two-thirds of men and two-thirds of women. You would get more protection if you immunize 100 percent of women, rather than immunizing two-thirds men or two-thirds women. To make the vaccine more relevant to men, Merck is incorporating HPV-6 and HPV-11, which are the main causes of genital warts, which are as big a problem for men as women. If there is a reduction in infection with those HPV types, then men would get a direct benefit.

Photos/Stills

1. The (green) B cell has ingested an antigen and displayed part of it (bright yellow) on a molecule bound to cell surface. Once a T cell (blue) becomes activated by binding to the antigen/molecule complex on an infected or cancerous cell, it begins to divide rapidly, and differentiates into memory T cells and other subtypes of T cells. Some, called T helper cells, secrete chemical messengers known as cytokines or lymphokines(golden yellow), which mobilize many other cells and substances.

2. J. Michael Hamilton, M.D., preparing the carcinoembryonic antigen (CEA) vaccinia vaccine used to try to prevent cancer.

Science Writers Seminar Presentations

1. Cancer Vaccines – Some General Issues

2. Cancer Vaccines: Jeffrey Schlom, Ph.D., Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH.

3. Design, Development and Delivery of Recombinant Vaccines for the Therapy of Human Carcinomas:Jeffrey Schlom, Ph.D., Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH.

4. Prophylactic Papillomavirus Vaccines: Douglas Lowy, M.D., Center for Cancer Research, National Cancer Institute, Bethesda, MD.

Cancer cells

Laboratories across the country soon will change the way they communicate with physicians about the 50 million cervical cancer screening tests performed each year in the United States. The revised system, known as the 2001 Bethesda System and published in the April 24, 2002, issue of the Journal of the American Medical Association (JAMA), conveys laboratory findings that help physicians and their patients decide what to do about the abnormalities found on Pap tests.

BenchMarks interviewed Diane Solomon, M.D., of the Division of Cancer Prevention at the National Cancer Institute (NCI), who is the first author on the JAMA article titled “The 2001 Bethesda System: Terminology for Reporting Results of Cervical Cytology.” Dr. Solomon has worked extensively in the field of cervical cytology and coordinated the development of The Bethesda System in 1988, as well as its revision in 1991 and the current 2001 revision. Dr. Solomon talked to BenchMarks about the changes included in Bethesda 2001 and what the revised system will mean for women and their doctors.

Why is the publication of these two papers considered a “milestone”?

Dr. Solomon: This is a milestone because it’s the first time, to my knowledge, that we have collaborative development of terminology that the lab uses and management guidelines for clinicians based on that terminology. I think that in this collaborative development, each process improved the other – there was cross-fertilization. The involvement of clinicians in the revisions to the Bethesda terminology as well as the participation of pathologists in the development of clinical guidelines will result in better communication between the laboratory and clinicians because both groups are invested in the terminology and the guidelines.

How, specifically, will these publications improve care of patients with Pap test abnormalities?

Dr. Solomon: It will improve the care of women because these guidelines are based on the most up-to-date information we have from research and clinical trials in the area of cervical abnormalities.

A specific example would be in the area of ambiguous test results. We have information from a clinical trial sponsored by the National Cancer Institute that identified a group of women with ambiguous test results that are at higher risk of having an underlying high-grade lesion, or abnormality, that needs to be treated. That finding led to a new term in the new 2001 Bethesda System called “atypical squamous cells cannot exclude HSIL” (ASC-H), which identifies this small number of women.

The guidelines, in turn, recommend that these women be managed differently based on this increased risk. That would be an example of how we have research coming together to inform terminology, and which then becomes the basis for the development of clinical management guidelines.

In addition, the terminology clarifies the communication between the laboratory and the clinician, so that there’s less confusion about what the Pap test findings mean – their clinical significance. For instance, in the previous version of Bethesda, there was a category known as benign cellular changes. This caused a lot of confusion amongst clinicians who really weren’t quite sure whether this was “Negative” or whether this reflected something that really required management – was this woman at increased risk? In the 2001 version of Bethesda, benign changes are more clearly identified as negative for atypical cervical changes. Even if there’s inflammation that’s causing some cellular changes, the findings are categorized as negative. Hopefully this will reduce concern and confusion in communications between the laboratory and clinician.

The fact that this is a uniform terminology that has been adopted by the vast majority of laboratories in the United States means that no matter where a woman is undergoing cervical screening, the terms will be the same.

Are you confident that most laboratories will use the new system?

Dr. Solomon: If past versions of The Bethesda System are any guide, over 90 percent of laboratories in the United States will use some form of the 2001 Bethesda System.

What do you feel is the most significant difference between Bethesda 2001 and the previous Bethesda Systems?

Dr. Solomon: Let me answer that by giving you the reason behind the Bethesda 2001 Workshop and the reason we felt it was necessary to actually revisit the Bethesda terminology.

First, over the past 10 years there has been tremendous development in new technologies for cervical cancer screening. Second, results from studies over the past 10 years have provided a better understanding of cervical abnormalities and their relationship to development of cervical cancer. We wanted to use these findings to improve communication between the pathologist and the clinician.

One example of a significant change in this version of The Bethesda System is the incorporation of the new technology called “liquid-based” collection. Instead of taking a conventional smear that spreads the cell specimen across a glass slide, liquid-based collection involves rinsing or dropping the collection instrument in a vial of liquid fixative. Previous versions of Bethesda required an evaluation of whether the specimen was considered adequate, but criteria were based on the conventional smear and did not address the new technologies. The 2001 Bethesda System incorporates new criteria for evaluating liquid-based specimens.

Another example – and this one reflects our new understanding of cervical abnormalities: There have been a number of studies over the past decade that have identified a subset of women who have ambiguous findings – either squamous atypical changes or glandular atypical changes – who are at higher risk of having an occult, or underdiagnosed, high-grade lesion, who need treatment.

To help identify this subset of women, Bethesda 2001 does two things. First, it eliminates any kind of false assurance to the clinician, by getting rid of the phrases “favor reactive process” or “favor benign process.” Second, it focuses clinicians’ attention on a subset of women with squamous cell changes who are at highest risk of having a lesion that needs treatment. It does this by creating a new category — atypical squamous cells — cannot exclude a high-grade lesion (ASC-H). So these higher-risk cells are now flagged for clinicians – not just in the new terminology but also in the management guidelines. These women are managed differently than the general pool of women who have ambiguous test results.

How do laboratories decide what cells are ASC-H?

Dr. Solomon: Generally, in the cervix, the more cytoplasm you have and the smaller the nucleus, the more benign (negative, normal) the process; tiny nucleus, lots of cytoplasm is benign. We call that low nuclear-to-cytoplasmic ratio. When the nucleus gets bigger and the cytoplasm gets smaller, we call that a high n:c ratio and those cells cause more concern. Low-grade lesions tend to have an enlarged nucleus, but they have abundant cytoplasm. They’re often easier to see because they’ve got a lot of cytoplasm.

However, highly abnormal cells or high-grade cells can be small, as can perfectly normal cells. When you have small cells with slightly enlarged nuclei, sometimes it’s clear that it’s a very bad cell – and we call it high-grade – but sometimes you can’t quite say whether it’s a reactive normal cell or whether it’s a bad cell. And that’s when we say “atypical squamous cell — cannot exclude a high-grade lesion.” We’re not sure whether it’s coming from a high-grade lesion, or whether it’s coming from something that’s mimicking a high-grade lesion.

How does Bethesda 2001 reflect our current knowledge of the biology of cervical cancer?

Dr. Solomon: We’ve learned a lot over the past 10 to 15 years about the biology of cervical cancer. We know that cervical cancer is clearly related to infection with a virus known as human papillomavirus, or HPV. While HPV is the main cause of cervical cancer, having an HPV infection does not necessarily lead to cervical cancer. In fact, HPV infection is very, very common, while cervical cancer is not. We understand that most people who are infected with HPV have the infection, but only transiently – it goes away on its own. The person’s immune system responds to the presence of the virus and, over the course of a year or so the infection resolves and the virus is no longer found. In some small number of cases the virus persists and cell changes occur that may lead to a precursor lesion to cancer. If not treated such precursor lesions may eventually lead to cancer.

The Bethesda terminology reflects our understanding of the role of HPV and cellular changes in the development of cervical cancer by emphasizing the fact that there is a dichotomy of low-grade lesions and high-grade lesions in the spectrum of squamous cell changes. Low-grade lesions are, by and large, transient infections with HPV that may cause some cellular changes. But in most cases the infection will go away on its own.

Uncommonly, HPV persists and you may have more abnormal cell changes known as a high-grade squamous intraepithelial lesion, or HSIL. This indicates that the HPV infection has not gone away on its own. This is the lesion that needs to be recognized and treated so that cancer never even develops.

The low-grade and high-grade dichotomy in the spectrum of squamous changes is not something new in Bethesda 2001. It actually was introduced in earlier versions of Bethesda but there has been controversy as to whether this was the proper categorization of the spectrum of squamous changes. What we’ve learned over the past ten years is that yes, the low-grade/high-grade dichotomy is actually the best way to translate what we know about the development of cervical cancer precursors and cervical cancer into terminology for cervical cancer screening. So sometimes we use knowledge to change things and sometimes our new findings actually just reinforce what we had before. In this case, our new knowledge has confirmed the terminology in earlier versions of Bethesda.

Were there concerns about previous Bethesda Systems?

Dr. Solomon: The original Bethesda System introduced a term known as “Atypical Squamous Cells of Undetermined Significance,” which is a very long way of saying that the laboratory is not quite sure what the findings represent. This term has been shortened to an acronym known as ASCUS, which clinicians as well as laboratories have found very frustrating because it’s not quite clear how to manage women who have this ambiguous ASCUS result.

And in fact the National Cancer Institute sponsored a clinical trial of women who have ASCUS, as well as low-grade squamous findings, to ask the question “What is the best way to manage women with these types of test results?” We’ve certainly learned a lot based on ALTS [ASCUS/LSIL Triage Study], which in fact has now informed the development of guidelines for managing women with these findings. So this is a case where the Bethesda terminology really prompted a clinical trial that has provided data that in turn was used in the development of clinical management guidelines.

It’s a frustrating fact for laboratorians, clinicians, doctors, and women that there are limitations to any medical test. No screening test is perfect, and one of the limitations in terms of the Pap test, or cervical cytology, is that the findings are not always crystal clear. There are cell changes that are ambiguous and we have to recognize that. We have to try to reduce that ambiguous category to the lowest possible number, but we also have to acknowledge that that’s one of the limitations of the test. I think the ALTS findings help us deal with that reality of the limitation of cervical screening.

Do you foresee another revision of The Bethesda System?

Dr. Solomon: Not immediately! However, it is true that The Bethesda System is a living document, and that means that it is flexible and can incorporate new developments or new findings based on research. But I think that with this third revision that we have reached a point where we have incorporated all that we currently know about HPV, about the development of cervical precancers and cancers. But I think it’s also important to recognize that should there be new data that comes to light, The Bethesda System is ready to evolve and incorporate new findings.

I know you used the internet to help develop this new system, the new terminology. Tell us how that worked.

Dr. Solomon: For earlier versions of Bethesda, in 1988 and 1991, we had a dozen people or so work on the pre-meeting process and then we held the workshop. It was always an open workshop, but we did not attract more than 50 to 150 people. For the third version of Bethesda, Bethesda 2001, we really wanted to use the Internet to open this up to the cytology community worldwide as well as to other interested individuals who have a stake in cervical cancer screening. We developed an Internet bulletin board site where all of the suggested changes to Bethesda were posted for anyone to review and comment on. The posted comments could be read by others at the bulletin board and individuals could respond to comments that had been left previously or they could leave their opinions about the recommended modifications.

We had over 1,000 individual comments that were posted on the bulletin board. This whole process took many months – leading up to the actual workshop. The workshop itself involved over 400 individuals who represented the spectrum of fields involved in cervical cancer screening. There were nurse practitioners, family practice docs, ob-gyns, pathologists, cytotechnologists, epidemiologists, public health and patient advocates and even a few lawyers present. So the participants truly represented the spectrum of those involved in cervical cancer screening.

What do you see as the next steps related to cervical cancer screening?

Dr. Solomon: We need to continue efforts to reach women who have not been screened. Unscreened women are among those at highest risk for cervical cancer.

We also need to reevaluate screening recommendations for how often women should have Pap tests done, when they should begin having Pap tests done, and if they ever reach a point at which Pap tests are no longer needed. I think one of the key areas that we need to address with regard to screening, is the question of how we incorporate new technologies into new cervical cancer screening recommendations.

What do you see as the next steps in terms of research in cervical cancer screening?

Dr. Solomon: I think one of the most exciting areas in cervical cancer research is the work on developing vaccines against human papillomavirus, or HPV, which we know is the cause of cervical cancer. I think that this is extremely promising and has the potential for having a tremendous impact in terms of women’s health – both in the United States, as well as worldwide.

In the United States we’re fortunate to have a strong cervical cancer screening infrastructure, where women have, by and large, access to Pap testing. But in many parts of the world that lack such an infrastructure, cervical cancer is the number one cause of cancer deaths among women. Development of a vaccine would have a significant impact on reducing deaths due to cervical cancer worldwide.

Animation/video

Anatomy and pap tests

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Anatomy and pap tests

A pap test is performed in this way: The uterus, or womb is located in the woman’s lower abdomen. The lower portion of the womb is called the cervix. The cervix opens into the vagina, which leads to the outside of the body. When the doctor or physician’s assistant does the pap test, a few cells are taken from the cervix.

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Reading pap test slides

A lab technician examines a slide under a microscope.

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Audio Clips

1. Interview with Diane Solomon, M.D., NCI, on “Reporting Pap Test Results and the 2001 Revision of the Bethesda System”:

      ( Audio – Length: 02:04 )

   Text Transcript

   Interview with Diane Solomon, M.D., NCI, on “Reporting Pap Test Results and the 2001 Revision of the Bethesda System”:

   Q: Have there been any concerns about previous Bethesda Systems?

   Dr. Solomon: The original Bethesda System introduced a term known as “Atypical Squamous Cells of Undetermined Significance,” which is a very long way of saying that the laboratory is not quite sure what the findings represent. This term has been shortened to an acronym known as ASCUS, which clinicians as well as laboratories have found very frustrating because it’s not quite clear how to manage women who have this ambiguous ASCUS result.

   And in fact the National Cancer Institute sponsored a clinical trial of women who have ASCUS, as well as low-grade squamous findings, to ask the question “What is the best way to manage women with these types of test results?” We’ve certainly learned a lot based on ALTS [ASCUS/LSIL Triage Study], which in fact has now informed the development of guidelines for managing women with these findings. So this is a case where the Bethesda terminology really prompted a clinical trial that has provided data that in turn was used in the development of clinical management guidelines.

   It’s a frustrating fact for laboratorians, clinicians, doctors, and women that there are limitations to any medical test. No screening test is perfect, and one of the limitations in terms of the Pap test, or cervical cytology, is that the findings are not always crystal clear. There are cell changes that are ambiguous and we have to recognize that. We have to try to reduce that ambiguous category to the lowest possible number, but we also have to acknowledge that that’s one of the limitations of the test. I think the ALTS findings help us deal with that reality of the limitation of cervical screening.

2. Interview with Diane Solomon, M.D., NCI, on “Reporting Pap Test Results and the 2001 Revision of the Bethesda System”:

      ( Audio – Length: 01:17 )

   Text Transcript

   Interview with Diane Solomon, M.D., NCI, on “Reporting Pap Test Results and the 2001 Revision of the Bethesda System”:

   Q: What do you see as the next steps in terms of research in cervical cancer screening?

   Dr. Solomon: I think one of the most exciting areas in cervical cancer research is the work on developing vaccines against human papillomavirus, or HPV, which we know is the cause of cervical cancer. I think that this is extremely promising and has the potential for having a tremendous impact in terms of women’s health – both in the United States, as well as worldwide.

   In the United States we’re fortunate to have a strong cervical cancer screening infrastructure, where women have, by and large, access to Pap testing. But in many parts of the world that lack such an infrastructure, cervical cancer is the number one cause of cancer deaths among women. Development of a vaccine would have a significant impact on reducing deaths due to cervical cancer worldwide.

Photos/Stills

NORMAL:
Squamous cells with small blue nuclei and abundant pink/green cytoplasm. A group of endocervical glandular cells can be seen in the lower left corner with a “honeycomb” arrangement.

ASC-US:
Squamous cells with some nuclear enlargement but still abundant cytoplasm.

LOW GRADE:
Squamous cells with enlarged dark blue nuclei, occasionally with a cleared ring of cytoplasm.

HIGH GRADE:
Very enlarged blue nuclei with less abundant cytoplasm, resulting in a high nuclear to cytoplasmic ratio.

SQUAMOUS CANCER:
Very enlarged nuclei with irregular distribution of nuclear material and nucleoli (red clumps in nuclei); dense spindled pink/orange cytoplasm.