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CAP Home > CAP Reference Resources and Publications > CAP TODAY > CAP TODAY 2005 Archive > The next picture show: New products are encountering a market ripe for digital imaging
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  The next picture show:
  New products are encountering

  a market ripe for digital imaging

title
  cap today

February 2005
Feature Story

For at least 10 years, it’s been routine for radiologists to click on digitized images of radiographs, relay them via the Internet to remote sites, print them on reports, archive and retrieve them, and use them for diagnosis.

But until recently, few pathologists have been able to derive the same benefits from digital technology. "Radiology is absolutely filmless, while pathologists are still hitting their eyeglasses to look through a microscope at slides," says Abhi Gholap, chief technology officer of the image analysis firm BioImagene, San Mateo, Calif.

A radiology image might be 50 megabytes, while a whole slide’s image goes beyond a gigabyte, he explains. "So the technology to manage that high-resolution image is exponentially more complex." As a result, only a small percentage of the 200 million or so slides read every year in the U.S. have been captured digitally.

Now, advances in digital photography and the plummeting cost of digital cameras are revolutionizing traditional ways of documenting pathology findings, collaborating on slide review, and analyzing images.

Drawn by an array of new commercial products, more and more anatomic pathology laboratories are making the decision to become entirely digital.

Product lines introduced only months ago are encountering a market ripe for digital imaging applications, even as innovations push development of the next new technology. Says Rob MacMillan, vice president of marketing for Impac Medical Systems, Mountain View Calif.: "Literally every couple of weeks, we see new versions of the digital cameras we work with that are cheaper, faster, and better."

New commercial applications of digital imaging for the laboratory include modular products and integrated packages that offer image capture, image management, image communication, image analysis, or a combination of these.

Image capture, of course, is the launching pad for the many capabilities digital imaging offers. A leading example is Nikon Instruments’ Coolscope, a microscope without an eyepiece. Requiring only a mouse and monitor to operate, it captures the image on a slide digitally and displays it. On the screen or monitor appear a micro image, a macro image, and controls. The point being enlarged is indicated with crosshairs on the macro image.

"The primary reason we developed it is we wanted to simplify the microscopy task—not necessarily in the U.S., but in some places where people aren’t as skilled in the clinical sciences," says Stan Schwartz, vice president of product and marketing for Nikon Instruments, Melville, NY.

The second reason was the ability to take a lot of pictures. "Coolscope VS is the ultimate easy way to take snapshots of your specimen. We said, let’s make it easy for people, so it’s a network appliance and it has an embedded processor. Just plug it into your network; it has its own IP address, and anybody from anywhere in the world can connect to that Coolscope and see the same image and in fact control Coolscope by using just an Internet browser, with no special software."

The third consideration was allowing pathologists to collaborate in reviewing slides, whether on tumor boards, for second opinions, or over the National Cancer Network. Coolscope permits people to share images without taking pictures of them, putting them on a hard drive, and e-mailing them.

"It makes the process transparent," with two people at locations remote from each other seeing the same thing at the same time, Schwartz says. "It’s like a combination of telepathology and collaboration."

"When Coolscope came together, we directed it at the educational market, so medical students and anybody could look at histology slides and learn with the best representative examples, any time of day, from anywhere they want. They’ve got the best images, not a microscope that isn’t working correctly or a slide that’s missing from their slide box."

"Human disease slides are hard to get now. Virtual technology makes them last forever, and they don’t fade," he says.

To truly emulate what pathologists do at the microscope, Nikon Instruments partnered with Bacus Laboratories Inc., Lombard, Ill., the inventor of virtual slide technology, Schwartz says.

"The pathologist says, ’I focus up and down, I move around a lot, and the most important thing is I don’t just look at a static image. Can you show me the entire specimen on the slide so I can go to a certain area?’ And the pathologist wants to do this in real time."

"We digitize the entire slide, picture by picture, store all the images in a folder on a hard drive, then use software that, in real time, stitches the images together and sends only the ones you’re going to look at to the monitor."

Virtual slide technology has been around for about 10 years, says Nikon senior scientist Stephen Ross, PhD, but in the past only experts could work with it. Now, about 20 percent of medical schools have already moved to virtual slide technology, Schwartz estimates. The American Board of Pathology also offers its board examination with virtual slides. (The virtual microscopy practice exam is online at www.abpath.org/VMinstr.htm.)

The Coolscope VS-Bacus package was released only last August, and demand has been high enough that it’s already on its third revision, with new functionalities added based on customer requests.

Is there any remaining advantage to keeping slides on film rather than in bytes? Schwartz compares digital image capture with music. "There are audiophiles who still buy tube amplifiers and can hear the difference. But most people can’t. The same thing holds true for digital imaging. We don’t sell many film cameras for microscopy anymore. It’s all digital."

Coolscope, which has international and U.S. sales numbering in the hundreds, sells for $25,495 bundled with the Bacus VS scan, browse, store and serve software.

For a test drive of Nikon’s Cool scope, see the live interactive Web site at coolscope.nikon.net or follow the link to Coolscope VS at www.nikonusa.com/microscopes. The Bacus virtual microscopy software can be sampled at www.bacuslabs.com.

Companies like Impac Medical Systems (formerly Tamtron) of Mountain View, Calif., have specialized in imaging modules that ease pathologists’ review and allow images to be included in reports.

Impac’s imaging module, on the market for two years, is integrated into the company’s AP Power Path product, which is installed in more than 350 academic medical centers, hospitals, and reference laboratories, says marketing VP MacMillan.

"The biggest demand that we’re seeing at this point is for the ability to include images in reports, so the consulting physicians don’t see a diagnostic quality image, but they do see an image that perhaps explains what the pathologist is discussing."

The module is designed to fit the workflow of pathologists as closely as possible. "We wanted to make the job of the pathologist very straightforward and simple, and we didn’t want the pathologist to have to turn into an expert on imaging or photography," MacMillan says.

They accomplished that by using an effective interface between the imaging device and their system. "If the pathologist while reviewing slides decides to take an image, it’s a very simple process to simply click on the module that captures it and have an image immediately associated with the case they’re working on," he says.

Impac’s imaging module is compatible with any device that fully supports the Twain standard. "I would view us as being very close to the pathologists as they’re doing their jobs. Pathologists reviewing cases want to look at images through a microscope and at the same time they can review information about patient history, all contained within our system."

"There’s been lots of talk for several years about telepathology," he adds. "The ability of a pathologist to consult with another pathologist perhaps across the world, and be able to review not only the details but actually look at and examine slides—at the moment we don’t see a big call for that. But clearly we may, as costs come down and we’re better able to handle these large images."

Diagnostic Instruments Inc., Sterling Heights, Mich., has been in business for 38 years as a microscope accessory company that primarily made optical couplers for microscopes, but it has broadened into digital image capture and management.

"In 1997 we introduced some of the first digital color cameras designed specifically for microscopy," says Philip Merlo, the company’s vice president for new business. He estimates the company has sold several thousand Spot digital cameras and couplers to pathologists around the world.

Since film quality color imaging is important to pathologists, Diagnostic Instruments has concentrated on three important specifications for creating true-to-life images of what the pathologist sees: resolution, field of view, and true color rendition.

With respect to color resolution, Spot cameras have introduced technology that maintains or extends the color resolution to that of film. The first technology is called three-shot color capture. "This technique samples each color plane at every pixel in the camera, avoiding the resolution loss that color mosaic cameras suffer," Merlo explains. The second technique used in the new Flex camera micro-shifts the image sensor in the camera "to effectively double the linear resolution providing 16Mp full-color sampled images," he says.

Pathologists would like to capture the field of view they see through their eyepieces, which is generally 22 mm. "In the past, they had to settle for 15 to 16 mm," Merlo says, "but now Spot cameras can provide the full 21.4 mm field of view."

To ensure the authenticity of its color rendition the Spot camera now incorporates the international color consortium systems standards as part of its color-rendering technology. Merlo says this technology is recognized as the world standard for digital color fidelity. "With properly set-up microscope illumination and monitor settings, Spot cameras can ensure that what you see is what you get," he says.

With the image captured, the pathologist now has to annotate, measure, add a calibration mark, store, or present it at tumor boards. "Spot cameras come with Spot software that provides nearly everything the typical microscopist needs as well as a standard Twain interface to your HIS system," Merlo says.

The precision of digital imaging, he says, actually permits analyses that couldn’t be done before. "With film, the pathologist was limited to qualitative diagnosis. Digital images, on the other hand, are quantitative and reproducible."

In the past, pathologists basically gave a rating of precancerous cells based on the image under the microscope. "That depends on the illuminator settings of the microscope as well as how the ambient illumination affected the color balance of the physician’s eye, whereas now with digitization we can provide the pathologist with a quantitative value," Merlo says.

A streamlined workflow is the real key for pathology, "one that is easy to use and doesn’t bog the pathologist down with menus and clicks," says Tom Vuke, vice president of imaging at MIS Inc., Franklin Park, Ill.

"More non-computer people are able to use digital cameras because we can get the number of clicks down to a minimum in order to get high-quality images into reports, presentations, and archives."

He stresses the virtues of MIS’ integrated solution in an affordable package: MIS offers "not only an easy way to get high-resolution images through our PAXcam digital cameras, but we also provide a means to work with the images after they are captured."

"So many people get a digital camera and say, ’I am there,’ but do not think about ’What am I going to do with all these images?’ PAX-it software is integrated with the cameras to manage the image collection so they can be archived in a database, annotated, sent to reports, sent to tumor board presentations, e-mailed, and more," Vuke says. Since typical applications for images in pathology are for communicating to others in reports and presentations, PAX-it has tools for annotating images with overlays that don’t destroy the original image data, so that portions of the images can be highlighted.

PAXcam cameras are designed for use on the microscope, and for digitization of gross specimens. "By using the PAXcam for gross and biopsies, images come directly into case folders in the managed collection, rather than accumulating on a memory card for later download, resulting in an improved workflow," Vuke says.

The demand to include digital images in pathology reports began in about 2000, says Arthur Hauck, MD, director of laboratory solutions development for Cerner Corp., Kansas City, Mo.

"At that time a number of specific reference laboratories started doing it, so the ability to include images actually became a marketing requirement for many pathology departments in order to compete."

Through its radiology Pacs systems, Cerner has offered diagnostic quality images for a number of years. "Those are actually a replacement for the film that radiologists traditionally used to make diagnoses. That’s a little different from what we’re doing today in pathology. We’re not promoting them by saying you can use them to make diagnoses. They are documentary. But the radiology Pacs systems give us the core technology to eventually offer that capability."

Cerner has created and is now conducting alpha testing of its MultiMedia Foundation, an archive and storage capability not just for pathology but for the entire electronic medical record. "Today that will include documentary-quality pathology images, but in the future we’ll store full slide scans," Dr. Hauck says.

Imaging solutions in pathology ideally should not be standalone systems, he notes. "As I’m working on a case and have it open on screen, that means I’m able to capture images and they’re automatically attached to a case. We’re also able to do case searches—say, to return a set of cases for breast cancer that have both gross and microscopic images."

Being able to organize cases with images into folders will also be a boon to pathologists, he says. "Pathologists can create their own folders of interesting cases, then build an online library of cases for teaching, for the tumor board, or just because you’re interested in a particular diagnosis."

Having these at your fingertips online is a plus over going to the slide file and pulling out a Kodachrome, Dr. Hauck says.

"With film, you have the problem that the colors tend to fade, the slides can buckle, or they can get scratched and broken, and just the time and effort to store and retrieve physical photographs are enormous. Digital images are basically there in their original quality forever."

The MacroPath system developed by the Italian company Milestone has been directly marketed in the United States only since late November 2004, says Jim Milios, Milestone’s international medical applications manager.

MacroPath, which retails at about $22,000, is an automated system of gross photography that allows control of a video camera through a foot pedal that enables zoom functions and photo capture for hands-free operation. The MacroPath also includes automatic insertion of a patient identifier number in each screen image. The software enables on-screen annotation features such as text comments, automatic precalibrated sizing, representative block sampling sites, freehand drawing, and automatic recognition of specific specimen accession numbers. It permits images to be stored in universal formats like .jpg, .tif, and .bmp, which can be easily incorporated into reports, stored to the laboratory information system, or shared online with other pathologists.

A version of MacroPath for forensic pathology, called MacroView, will make its U.S. appearance shortly. "The autopsy is currently a very manual process requiring a lot of dictation work, and imaging technology will reduce that to a minimum, relying more heavily on visual images and ultimately leading to less time in grossing and more time in the microscopy room," Milios says.

He admits to some challenges in conveying the benefits of digital imaging to pathologists. "Our company president noticed in histology grossing rooms that they continue to use technology that’s been around for 100 years. He saw it could be improved but felt it had to be kept very simple and be very intuitive and easy to use."

"As a general rule," says Todd Schreiber, Milestone’s eastern regional sales manager, U.S., "pathologists are more comfortable with the light microscope. It’s been around for hundreds of years, and so for a number of imaging systems, the biggest competition is not another company but the microscope itself. It’s a paradigm shift to look at a monitor rather than through the oculars of a light microscope."

Milestone’s system, he says, offers enough ease of use to overcome that obstacle. It is already being used routinely in the United Kingdom, where the shortage of pathologists in the grossing room means histotechnologists are now doing the grossing. "Quite frankly we’re anticipating a great response in the U.S., but up until six weeks ago it had never been actively promoted here," Milios says.

Digital imaging takes much of the subjective nature out of what’s happening in the autopsy or grossing room, says Jes Strong, Milestone’s western regional sales manager, U.S. "If the pathologist is describing tissue, what he says is red, transcribed on a piece of paper, may be orange to someone else." With digital imaging, "you’re basically standardizing the process," Strong says.

Schreiber says pathologists will demand a degree of accuracy and precision in imaging that "the human eye is just not built to do."

"You’re not going to be able to build an imaging system that can duplicate the human eye’s pattern recognition. But the eye is inherently weaker with different levels of color or intensity," he says.

Cancer diagnostics and prognostics are among the newer applications of digital imaging. BioImagene’s Pathiam (Pathological Image Analysis and Management System), a tissue analysis program, has several hundred users in the U.S. and internationally.

"We have software designed by pathologists for pathologists," says Mohan Uttarwar, BioImagene’s CEO, noting that the company adopts a holistic approach by emulating what pathologists do all day and trying to "look from their eyes."

The company’s digital pathology platform, iHarness, analyzes color, intensity, size, shape, morphology, and structure of tissues, making it possible for pathologists and researchers to interpret images quickly and consistently.

Pathiam, software that works with existing scanners, uses a neural network approach and smart algorithms of pattern recognition.

"The process of extracting knowledge out of the millions of slides read every year is very, very manual," Uttarwar says. "We think there are a lot of efficiency, subjectivity, and security issues there. It’s a massively untapped market."

While nothing can match the human eye’s ability to perceive complex patterns, he stresses that there are limits to the eye’s power. "Fatigue, the mundane nature of the task, and the large number of cells in a given sample can limit a pathologist’s ability to consistently make the subtle distinctions necessary for accurate analysis."

National reference laboratory US Labs (recently acquired by Laboratory Corporation of America) announced five months ago the launch of Virtual Image, a system offered to its network of pathologists and pathology centers that uses BioImagene’s iHarness to emulate a 20x microscope. US Labs says iHarness allows it to reduce average analysis time from 20 minutes per case to about two minutes per case.

ChromaVision Oncology Services (recently renamed Clarient), Irvine, Calif., is offering virtual microscopy as well, says its medical director, Kenneth J. Bloom, MD. "Groups that use reference laboratories to do staining expect rapid turnaround time and reasonable prices. With virtual microscopy we can enable access to images over the Internet."

"In the past clients would have received a FedEx box with immunostained slides to review under a microscope. Now it is possible to get the images 24 hours earlier and view them on a computer screen, order more tests if needed directly online, and have results as soon as they’re available for review."

It gives pathology labs with limited resources in immunohistochemistry access to a state-of-the-art laboratory so they can provide timely, accurate diagnoses for their patients and compete in their marketplace, Dr. Bloom says.

Up to now, "image analysis has had a very rough road," he notes. As a member of the Diagnostic Immunology Resource Committee for the CAP’s Surveys program, Dr. Bloom reports that the number of image analysis Surveys subscribers has been small—about 30 to 40—compared with Cell Marker’s 800 subscribers.

"The majority of pathologists doing immunohistochemistry are not yet looking to image analysis as an aid. There must be a defined clinical need for its use."

Variability in interpretation has been a problem, especially in the emerging field of targeted therapies. Immunohistochemical testing of HER2/neu to determine eligibility for Herceptin therapy, Dr. Bloom says, has been controversial for this reason.

A recently published study he conducted showed that pathologists looking at the same set of HER2/neu slides manually by light microscopy had interpretations that ranged all across the board. "But when the same slides were looked at with image analysis, all pathologists got roughly the same result and everybody showed improved accuracy."

Because of the expected surge in targeted therapies for cancer and other diseases—and the projected need for diagnostic tests to go along with the 100-some drugs now in development—Clarient recently reorganized itself to include a diagnostic reference laboratory, a bioanalytical division, and image analysis instrumentation.

In Dr. Bloom’s view, applications that help predict therapeutic outcomes are now becoming practical. "When you talk about imaging solutions, you’re always limited by a cost-benefit ratio. If you go back five or six years ago, we had significantly less computing power and poorer image quality."

"Now we clearly have much better scanning technology that allows for improved imaging algorithms, and we have the computer horsepower to execute them," he says.

Clarient’s ACIS system is a flexible image analysis platform offering intensity measurement, rare cell detection, morphometry, object counting, and tissue microarray capabilities, which can be used individually or in combination in analyzing immunostained slides.

The ACIS system lists at prices from $200,000 to about $250,000, Dr. Bloom says. More than 40 systems are in place worldwide at research and biopharmaceutical facilities, and about 250 clinical installations have the full ACIS or the Access Remote Pathology Program.

With the Access program, community pathologists can send specimens to Clarient’s diagnostic reference laboratory, where, after they’re stained and scanned on the ACIS automated microscope, they are available for review by a pathologist, over the Internet or on a remote ACIS workstation.

A video of Clarient’s ACIS system in operation is online at www.chromavision.com/library/home/ACIS2.asf.

Laboratories will soon need to offer better tests to determine which patients can benefit from a broad range of targeted therapies. When treatments may run $20,000 to $40,000 per year, "if you can confidently detect the target, you can save an exorbitant amount of money on therapy," Dr. Bloom says, noting that the drug Herceptin would never have been approved without the HER2/neu test because the majority of breast cancer patients are HER2-negative and would not have benefited from the drug.

Digital imaging enables the precise measurements needed. Dr. Bloom expects to see soon not only improvements in resolution and computer power that will result in better images and better ways to analyze them, but also more multidimensional analysis.

"Currently we look and say, ’Here’s a breast cancer.’ We look at ER status, PR status, HER2/neu expression, and the proliferative index as binary decision points that then translate into what physicians will do."

Clinicians need to move beyond looking at these kinds of discrete variables, he contends. For example, while expression of estrogen receptor is used to qualify a patient for anti-estrogen therapy such as tamoxifen, "we now know that if the tumor also overexpresses HER2/neu protein, tamoxifen is unlikely to be effective. However, the patient may benefit from taking aromatase inhibitors," he says.

"What we’ll see is the combination of tests that will help determine therapy," he adds. Combinatorial assays, especially those assessing the expression of multiple genes, are already showing clinical promise in breast cancer treatment.

Ventana Medical Systems Inc., Tucson, Ariz., is partnering with TriPath Imaging Inc., Burlington, NC, to validate and launch an image-analysis system that integrates state-of-the-art microscopy with high-resolution digital imaging and quantitative analysis of diagnostic cancer markers. The Ventana Imaging Analysis System, or VIAS, is an aid to the pathologist in detecting, classifying, and counting cells of interest based on marker intensity, size, and shape. It requires no change to the pathologist’s daily procedures.

Lupe Manriquez, MD, a pathologist with Ventana, says, "When evaluating immunohistochemically stain ed samples for a diagnosis, the pathologist places a slide on the microscope stage and selects an area of interest for quantitative scoring." He or she then takes high-resolution photos of the representative areas, archives the images, and selects those to be included on the integrated patient report. "This is accomplished with seamless integration into the pathologist’s current workflow," she says.

VIAS is optimized for Ventana and TriPath imaging assays. When used in conjunction with Ventana’s BenchMark series of instruments, VIAS will standardize diagnostic results.

"This system allows an integrated patient report to be created, which can be customized by the pathologist," Dr. Manriquez says. The report includes patient information, a results summary section, as well as biomarker-specific quantitative information, histograms, and color images of immunohistochemical staining.

"The image-analysis system is really an aid to pathologists," Dr. Manriquez says. "We’re looking to facilitate workflow and provide quality reports that can also be reviewed with a patient to create better understanding of the diagnosis." Ventana expects the product to be on the market in May of this year.

"We’re still a long, long way from the time when a machine can scan a slide and arrive at the same conclusions a pa thologist does, although some pathologists chuckle about that," Impac’s MacMillan says. "When you think about a pathologist examining a slide, there is an awful lot of expertise and intuition that goes into their analysis."

But digital imaging companies promise tantalizing advances in the next few years. Among them: real-time streaming of live microscopic views for telepathology directly from digital cameras, morphometric and densitometric quantitation, and possibly even computer-generated histological diagnosis as a back-up tool for the pathologist or in quality control. All of those technologies are in the works.

Anne Paxton is a writer in Seattle. For digital imaging beginners, the CAP is now offering a Web-based course, "Digital Camera and Image Basics: Virtual Informatics College (www.cap.org). Its aim is to help residents and practicing pathologists understand the technology and identify considerations for purchasing a digital camera and assembling a digital image workstation.

 

 

 

 

   
 
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