Digital Mammography in the 21st Century

Digital Mammography in the 21st Century

Digital Mammography in the 21st Century

On September 4, 2001, the National Cancer Institute (NCI) and the American College of Radiology Imaging Network (ACRIN) launched a multicenter study to determine if digital mammography meets or exceeds capabilities, costs, benefits, and other factors, when compared to standard film mammography for the detection of breast cancer. Digital mammography is a technique for recording x-ray images in computer code instead of on x-ray film, as with conventional mammography. The images are displayed on a computer monitor (sometimes referred to as a workstation or viewbox) and can be enhanced before they are printed on film.

Etta Pisano, M.D., is the principal investigator for the study and Professor of Radiology in the Breast Cancer Program, Radiobiology & Imaging Program, at the University of North Carolina (UNC), Chapel Hill. Behind the News talked with Dr. Pisano about various aspects of the new study and other issues related to digital mammography.

Digital mammography promises a lower radiation dose due to improved X-ray absorption. What would this mean for a 40 year old woman over the course of her life when comparing the amount of radiation from film versus digital mammography?

Dr. Pisano: We don’t have very much information on that yet. We think it’s going to reduce the dose, but we don’t know that for sure. In the ACRIN trial, we are planning to match the dose — not let the digital dose be any higher than the film dose. We can certainly get the same info out of a digital mammogram at a lower dose than film but we might be able to get more information at a higher dose. One of the limiting factors with film is that the higher the dose you apply, the worse the image gets – there’s a natural limitation. With digital, you can increase and increase the dose and you might get more information. There’s not that same limiting factor that film has. Dose (for film) was set arbitrarily many years ago and there’s no magic perfect dose. The key thing is to find the cancer, so my feeling is that if we can find cancer at a slightly higher dose within a range that’s acceptable, we might end up doing digital mammography at a higher dose (than film), not at a lower dose.

Image manipulation with digital mammography promises fewer false positives and better readings for women with dense breasts — how easily can images can be manipulated and what are the most realistic reductions in false positives and readings of dense breasts that can be expected?

Dr. Pisano: At this, point, the reason we’re doing the ACRIN study is to make sure there’s an advantage of using digital mammography instead of film, since we’re not sure at this point in time. We expect there to be an advantage but none of the early studies has shown a real benefit of digital over film. We think there will be an advantage with dense breasted women. You’ll be able to look at an image of the dense breast and look at it in multiple different ways to see if the patient really needs to come back or not depending on whether it’s a mass or some other density on the image. We think we’ll be able to do that and anecdotally, that seems to be the case. There have been fewer false positives in the studies that have been completed to date but it’s not clear what population that’s from but from a physics perspective, it makes the most sense that it would effect a dense breast population before any other population.

General Electric (GE) offers the only FDA-approved digital device — what other devices are awaiting approval and will be tested in Acrin?

Dr. Pisano: Three of the four machines we’re looking at are all digital. GE is the only one that is FDA approved. They all have digital detectors. The Fuji system uses traditional mammography unit whereas the other three we’re testing will require, once they get FDA approval, buying a whole new system. The Fuji system is actually a plate system that replaces the film detector so that part of it is the only thing that’s different from a traditional mammography system.

One of the goals of our trial is cost-effectiveness. The Fuji system will probably require the smallest capital investment. You have to replace your processor with a printer and you have to replace the film with a detector system so you still have film but it’s printed film instead of processed film.

How important is reader training in advancing digital mammography? How much re-training will have to be done for readers who are used to reading X-ray mammograms on light boxes?

Dr. Pisano: It’s not so much that the images look that different but the key is how to manipulate them on new digital viewboxes. The real issue is ease of use of the workstation viewboxes. I think radiologists are so familiar with these kinds (breast) of images that it’s not reading them so much as using them. These viewboxes need to be improved. They’re too complicated with too many buttons. They’re just in their infancy and will be improved. The devices we have are two monitor view systems and some use three monitors. It’s deciding what images to bring up and that’s what takes knowledge and learning. The reading is still pretty straightforward. We don’t have data on learning curves, but I would guess that in a few months a radiologist could be comfortable on the digital systems. I want to emphasize however, that the viewboxes could be improved substantially so that there won’t be such a long learning curve. And they will be more user-friendly. I’ve talked to GE and Fisher about improving their systems and I think as more and more people use them, more people will request easier to use systems. And I think the companies will want to respond to the market. So I think it’s just a matter of time before these systems improve

Telemammography allows for transmission of digital mammograms over electronic lines. How will this benefit rural and other areas where expert readers and other technical facilities may not be available? How important is digital mammography in aiding the acceptance of telemammography?

Dr. Pisano: Women now have access to their old films with a slight delay in picking them up via trucks or via FedEx. What I think telemammography will bring to us is in remote centers, like in rural North Carolina, we had 10 contiguous counties in eastern North Carolina without a mammography center. It would certainly be convenient if instead of having to send images back from a mobile unit via a car we could have them beamed back via satellite or internet lines. Clearly that will bring access to women who currently don’t have access without a huge inconvenience to them. Another place where it may be useful is in the military.

The other thing that will happen is that you’ll have access to experts much more readily if you want to beam your mammogram to experts in another city; breast imaging radiologists will be able to consult each other. If I have a partner based across town and I want her opinion, I can just ask her to look on-line and there it is.

The National Library of Medicine at NIH setting up a central facility to store digital mammograms. How important is this facility and how could these mammograms be utilized in the future?

Dr. Pisano: I’m involved in that effort. It’s the National Digital Mammography Archives. I think it’s a good pilot project to see if it’s going to be tenable or practical. There’s lots of security issues with new regulations to protect patient confidentiality and so this project is really piloting how to deal with confidentiality issues when you’re dealing with large numbers of patient records centrally. It’s going to be interesting to see how well it will work. I think it will work well and the key thing is to get facilities (universities, hospitals, and other institutions) to see the utility of having a centralized resource. The patients immediately see the value but, for example, does UNC hospitals see the utility? The traditional thing, done over the past 100 years, is that hospitals have had complete control over their own records. They still would have control even when they’re stored off-site but maybe they see it as losing a little bit of control. We already do this with film however when they’re stored across town and we have a truck going back and forth across town 10 times a day. Will each institution decide they want to have their own server farm rather than support a centralized facility where there are economies of scale? I believe you can save money when you pool resources for data storage. It’s nice having NLM supporting this project so early in the development of digital mammography because it will allow us to test the feasibility of this approach. The goal of the project however is not to compare diagnostic outcomes of any of the images – it’s more of a feasibility study to show that centralized storage and retrieval can be workable.

We’re also building a digital mammography teaching tool. How we teach people in post-grad courses and in schools is we take cases and show them what a typical cancer looks like. This will allow a much bigger resource in getting many cases quickly and we’re building cases from this resource. This is an example of what could be accomplished with this centralized facility as opposed to a localized system. It’s really a nice resource for training and improving the competence of your staff.

One problem that has arisen lately is that mammography units and centers are no longer that profitable and reportedly are shutting down in many areas around the country, making access to mammograms more difficult for some women. How might digital mammography help or hurt this trend?

Dr. Pisano: This is a real issue. Digital is definitely going to be more expensive. There is no question that the technology, the hardware, costs more than film’s technology costs. There are cost gains however. Some would argue that the cost savings will override initial costs by dint of not having to use film and by being able to see more patients. I tend to be pessimistic in reduction in costs because the hardware is so much more expensive that you’re going to have to save a lot in film and call-backs to make up for the hardware costs. We believe there will be fewer call-backs because the preliminary studies have suggested it. So does that save enough? Clearly it saves all the patient anxiety, the patient related issues like time away from work and biopsy issues will be less if that bears out in our trial but the issue of whether it will save money to the centers is an open one.

In terms of keeping a mammography center open, the Harkin bill right now being considered by the Senate to improve reimbursement may go a long way to help things improve. Radiology is a huge field and there are parts of radiology that pay significantly better than breast imaging because breast imaging is a screening modality versus diagnostic modalities like CT and MRI. We have to compete for manpower or we won’t be able to keep this service open for patients. We either need to increase the number of people in the (radiology) field to do breast imaging or motivate people to go in to the field and it sounds like that’s where the Harkin bill is aimed. If it has only a slight improvement in the incentives, it should have a big impact on manpower, in my opinion.

What other mammography techniques are in development that could add to or even supplant digital mammography? Are thermal or infrared techniques some possibilities?

Dr. Pisano: I don’t think there’s enough information about these other systems as they apply to breast imaging to make any conclusions.
The 3 key tasks in breast imaging are:

  • to find the breast cancer

  • to figure out what is cancer and what’s not cancer

  • once the cancer is diagnosed, to tell the extent of disease

These are 3 places that any new technology could place itself and affect patient management. So a new technology may not work in screening but may help determine extent of disease. The on-the-horizon technologies don’t have enough info to make a hard judgement. Look at how long it’s taken us to see where MRI fits in. People don’t know yet. I’m involved in two trials to see if it can help tell cancer from non-cancer and also in a screening trial to see whether MRI used in high risk women could find cancer earlier. We’ll see if MRI should be more widely adopted once these trials are completed.

Animation/Video

1. Introduction (Click movie to begin)


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1. Introduction (Click movie to begin)

[Animation clip begins by zooming in on a vertically oriented DNA helix set on an empty black background. The helix is comprised of two ribbon-like vertical spiraling blue structures, each of which has a series of colored rungs running its entire length. The rungs, or bases, which extend horizontally from each spiral, are red, yellow, green and purple. The bases on one spiral are bound to those on the other, creating horizontal base pairs that connect the two spirals. The base pairs are matched by color: red/green and yellow/purple. The bases are also shaped differently, so that a red base fits exclusively into a green base and a purple base fits exclusively into a yellow base.]

Changes in DNA, some of which are inherited, others of which are due to outside causes, can lead to cancer. The cancer process begins when a cell starts to divide.

[Zoom in on DNA helix]

In division, the DNA begins to unwind [Base pairs begin to separate, unwinding the DNA helix] and a strand of what’s called Messenger RNA begins to copy one of the DNA strands [Messenger RNA, shown as a spiraling ribbonlike purple structure, creates matching base pairs on half of the DNA helix].

If the copying process goes wrong, cancer can occur.



2. Deletion Mutation


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2. Deletion Mutation

[Animation clip begins by zooming in on a vertically oriented DNA helix set on an empty black background. The helix is comprised of two ribbon-like vertical spiraling blue structures, each of which has a series of colored rungs running its entire length. The rungs, or bases, which extend horizontally from each spiral, are red, yellow, green and purple. The bases on one spiral are bound to those on the other, creating horizontal base pairs that connect the two spirals. The base pairs are matched by color: red/green and yellow/purple. The bases are also shaped differently, so that a red base fits exclusively into a green base and a purple base fits exclusively into a yellow base.]

Instead of fully copying a DNA strand, the copier strand cannot copy bases that are missing on the DNA.

[Messenger RNA, shown as a spiraling ribbon-like purple structure, creates matching base pairs on half of the helix, but no connection occurs where there is a missing base.]

What results is called an oncogene, which is a mutated gene which may have missing base pairs or other abnormalities. The oncogene is then processed by something called a ribosome, shown here as a large blue structure [The Messenger RNA moves away from the DNA helix and toward a ribosome, shown here as a large blue structure].

The resulting protein will have abnormalities, depicted here as transparent globes, which can lead to cancer.

[The Messenger RNA enters the left side of the ribosome. A string of red, blue, green, and purple globes emerge from the right side. Transparent, colorless globes are interspersed among the colored globes].



3. Free Radical Mutation


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3. Free Radical Mutation

[Animation clip begins by zooming in on a vertically oriented DNA helix set on an empty black background. The helix is comprised of two ribbon-like vertical spiraling blue structures, each of which has a series of colored rungs running its entire length. The rungs, or bases, which extend horizontally from each spiral, are red, yellow, green and purple. The bases on one spiral are bound to those on the other, creating horizontal base pairs that connect the two spirals. The base pairs are matched by color: red/green and yellow/purple. The bases are also shaped differently, so that a red base fits exclusively into a green base and a purple base fits exclusively into a yellow base.]

During the copying process, a free radical, spun off perhaps by ionizing radiation, strikes the DNA and causes an incorrect pairing of two bases.

[As the base pairs separate, a free radical, shown as a yellow ball, comes in from the left and strikes a red base on the leftmost blue spiral of the DNA helix. After the free radical strikes, the red base changes color and shape from a pointed red cylinder to a grey diamond shape. As Messenger RNA, shown as a purple ribbon-like structure, moves in, a large yellow hexagonal node is created to bind with the diamond node].

Had the error not occurred in this particular tumor-suppressor gene, cancer might have been averted because this particular gene helps turn of the cancer process.



4. Mismatch Repair


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4. Mismatch Repair

[Animation clip begins by zooming in on a vertically oriented DNA helix set on an empty black background. The helix is comprised of two ribbon-like vertical spiraling blue structures, each of which has a series of colored rungs running its entire length. The rungs, or bases, which extend horizontally from each spiral, are red, yellow, green and purple. The bases on one spiral are bound to those on the other, creating horizontal base pairs that connect the two spirals. The base pairs are matched by color: red/green and yellow/purple. The bases are also shaped differently, so that a red bases fits exclusively into a green base and a purple bases fits exclusively into a yellow base.]

[Zoom in on a group of base pairs in the DNA helix. As the base pairs separate, Messenger RNA, shown as a purple ribbon-like structure, moves in and creates matching base pairs on half of the helix. But one of the pairs, a green node with a purple node, is mismatched by color and shape.]

A mismatch of base pairs, shown here as a green base pairing with a purple base instead of a proper yellow/purple pairing, can occur during the DNA copying process.

A mismatch repair gene then might signal a protein to help repair the process [A mismatch repair gene, shown as a purple net-like structure, comes in from the left and settles on the mismatched base pair].

But before the repair process can be completed, an outside agent, such as the chemical benzene, interferes and defeats the repair, leading to a cancerous cell.

[The mismatched green base begins to turn yellow. A group of oblong yellow hexagons with brown circular centers comes in from the right and swarms around the group of base pairs. The mismatch repair gene moves out to the right and the mismatched base returns to its original green color].



5. Cell Growth and Repair


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5. Cell Growth and Repair

[Animation clip begins with a close view of a vertically oriented DNA helix set on an empty black background. The helix is comprised of two ribbon-like vertical spiraling blue structures, each of which has a series of colored rungs running its entire length. The rungs, or bases, which extend horizontally from each spiral, are red, yellow, green and purple. The bases on one spiral are bound to those on the other, creating horizontal base pairs that connect the two spirals. The base pairs are matched by color: red/green and yellow/purple. The bases are also shaped differently, so that a red base fits exclusively into a green base and a purple base fits exclusively into a yellow base. In addition to the uniform base pairs, the DNA helix also displays a mutated base pair, made up of a small grey diamond-shaped base paired with a large yellow hexagon, and two bases on one blue spiral, a purple base and a yellow base, that do not have matching nodes on the other blue spiral, creating a gap in the connections.]

In all three of our examples, something went wrong–the DNA lead to a mutated RNA copy and formation of new mutated or cancerous cells arose.

[The view zooms out until the DNA helix fades into the center of a cancer cell, depicted as an asymmetrical greyish-blue mass with a darker blue center. Two of these structures appear, joined by their greyish-blue layers, on a background of healthy cells, depicted as asymmetrical pink masses with purple centers. The cancer cells separate into two distinct cells. The shot pulls back as the cancer cells continue to multiply, covering the healthy cells.]

Cancer cells divide at a much quicker rate than normal cells, forming irregularly sized cells with enlarged nuclei. As cancer cells continue to divide, they form masses called tumors.

[The shot continues to pull back until the cancer cells appear as a greyish-blue mass on the left side of a person's chest. A white circle, representing an implanted surgical port, is surrounded by concentric grey circles and appears on the person's chest. A white syringe appears and moves in to inject...]

Tumors can sometimes be treated with new molecular agents such as the breast cancer drug Herceptin. This drug can be injected into a patient to try and repair the DNA copying process that got out of control, destroy the tumor so that only normal cells remain and future cell division only originates from normal, unmutated DNA.

[The shot zooms in on the person's chest until normal cells reappear, and continues to close in until a normal, unmutated helix is seen.]


Photos/Stills

1. DNA Duplication

DNA Duplication


2. Deletion Mutation

Deletion Mutation


3. Free Radical Mutation

Free Radical Mutation


4. Mismatch Repair

Mismatch Repair


5. Cancer Cell Growth and Repair

Cancer Cell Growth and Repair

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