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By Mark Terry
Writer - Washington G2 Reports
07/14/08
GE Healthcare and the University of Pittsburgh Medical Center (UPMC) recently announced they were beginning a joint venture in digital pathology. Together, they formed Omnyx, LLC, which would build and market a system for digital pathology. To date, digital pathology is a market that's only been nibbled at the edges, and is primarily the domain of microscope companies such as Zeiss, Nikon, and Olympus. However, a small number of companies, bolstered by advances in digital image-gathering, are entering what is predicted to become a $2 to $4 billion industry.
Digital Pathology
Simply put, digital pathology is the utilization of digital photography to capture images on microscope slides. In the past (the early 1990s), there were a number of technical problems with digital imaging of anatomic pathology samples. Digital cameras captured the microscope slide images and stored them. However, the resolution of the digital photographs was not competitive with microscope optics and storage space was limited. A massive amount of data storage was required if the images of an entire microscope slide were to be archived. In addition, the task of capturing the entire microscope slide contents was time-consuming and laborious.
In "Use of whole slide imaging in surgical pathology quality assurance: design and pilot validation studies," by Jonhan Ho, et al. (Human Pathology 2006; 37: 322-331), Ho says: "Single-field, camera-on-microscope systems do not document the entire slide, forcing the pathologist to find and capture limited fields of interest. This causes the pathologist to become a photographer, takes significant time, and results in images that subsample the case and do not necessarily stand on their own."
A little later, in the mid-1990s, robotic microscopy was attempted. Again, although the actual scanning and photographing of the microscope slide was automated, the resolution limitations and storage issues were still inadequate for the daily needs of working pathologists.
Around 1997, researchers began experimenting with whole slide imaging (WSI). As described in Ho's article, a system by Joel Saltz and his group at Ohio State University developed a robotic microscope that captured large areas of the microscope slide, field by field, then utilized the computer to stitch the individual captured images into a "montage." The primary disadvantage to this was the number of hours involved in capturing and merging the images. It was a step in the right direction, however.
Computing power and digital optics began to catch up a few years later. Ho cites an automated high-speed system developed in 2000 by researchers affiliated with UPMC. "It was based on traditional microscope optics, a strobe light linked to a precision stage, and a digital video camera." It was able to image an entire slide at 20X magnification in 5 to 10 minutes.
Newer systems build on this concept with greater resolution, the utilization of barcode readers on the slides, and an expansion of the optics involved. Ho et al says, "Newer devices are implementing nontraditional optics, illumination, and sensors designed specifically for very high speed image capture and should result in significant improvements in speed, throughput, and resolution in the months and years ahead, with different manufacturers eventually focusing on different aspects of the market."
Dick Soenksen, CEO of digital pathology company Aperio Technologies, Inc., believes there are four requirements for effective digital pathology systems. They are:
- Scanning ability.
- Software to manage digital slides. In digital radiology they are called PACS (picture archiving and communication systems).
- Information management systems.
- The ability to perform image analysis on the digital slides.
Aperio Technologies, Inc.
If there is a leader in digital pathology systems--and it's not clear that there is one--Aperio is probably it. Their headquarters is in Vista, California, with a European office in Bristol, U.K. Dick Soenksen, CEO of Aperio, says, "We are focused on digital pathology. That's the only thing we do and it's the only thing we've ever done. From our perspective, digital pathology is managing the information that's generated by being able to digitize entire slides."
Aperio essentially offers an entire system for digital pathology, including the ScanScope group of digital slide scanners, the Spectrum Plus Operating System, various applications software, and services that will perform the digital slide capture for the pathologists or institutions. Soenksen says, "This has the potential to transform what pathologists do, because you can take this information in the form of a digital slide image and do all sorts of cool things with it. You can share it on the Internet, you can analyze it with image analysis algorithms, you can present the information at a conference. It basically makes the pathologist independent of having to be in the same room with a microscope and a glass slide. That has the potential to drive an enormous number of efficiencies over the way pathology services are delivered today."
Soenksen notes that earlier digital pathology technology wasn't as good as traditional microscopy, but that's changing. "Now, the digitized slide is as good as the glass slide. It has as much if not more information content as the glass slide and can be accessed independent of the glass slide. You can have thousands of digital slides on a server and have large numbers of people looking at multiple slides or even different regions of the same slide. Information access is significantly more powerful than with a glass slide."
Soenksen indicates that one of the real benefits in whole slide imaging is the ability to utilize different staining techniques, but look at the same spots on the slide. An example is a breast cancer slide that has both H&E stain and one that has fluorescent in situ hybridization (FISH) for ERPR/HER2. "Typically when a pathologist looks at those, he will pick up a slide, he'll look at some cells and say, 'Yes, they look positive.' Then he will look at the same slides under the microscope. With digital pathology you can put them up on the monitor side-by-side. You have continuous sections stained with different antibodies, so you can scroll in synchrony and look at the cell in H&E and the same cells in ERPR/HER2 and pan synchronously. It's a very powerful visualization capability associated with digital pathology."
One of the more interesting components of Aperio is their Digital Slide Scanning Service. Rather than invest in a system, the pathologist can ship their slides to Aperio and the company will use the ScanScope Scanner to digitize the slides, which are then returned along with a CD or DVD or via Internet access. Although the digital pathology market's goal is undoubtedly to have all pathologists, labs, and hospitals using their technology in-house, this is a potential way to get pathologists to digitize early.
BioImagene
Cupertino, California-based BioImagene focuses on imaging systems for life sciences and digital pathology solutions. Mohan Uttarwar, President and CEO of BioImagene, says that their core competencies are, "The digitization of microscope slides, bringing in high-resolution image management, searching, mining of imaging data, and image analysis. Finally, the power of the Internet can be used to manage information, whether it's a clinical report, educational content, peer reviews--formal or informal--or second opinions. All these pieces put together are something we as a company have focused on."
Uttarwar believes rapid adoption of digital pathology is on the horizon. He notes that technological development is providing high quality imaging now. "What is missing now is a really comprehensive application. Like the spreadsheets for an accountant, the accountants went through the paradigm shift thinking that spreadsheets would replace them. It didn't happen that way. It just made accountants more efficient and better. I think it's the same with pathologists."
In addition, Uttarwar thinks the price point is coming down, making digital pathology solutions more affordable. "Historically, digitizers, because of the high resolutions, have been very expensive and cost hundreds of thousands of dollars. We are the first company that has made digital pathology a practical reality and an affordable reality. You don't have to spend hundreds of thousands of dollars. We came up with a model where practicing pathologists get the entire packaged system ready to roll that's pay-as-you-go."
Uttarwar cites four issues that are slowing adoption.
- Lack of standardization.
- Psychology, or resistance on the part of pathologists.
- Ease of use and high quality.
- Pricepoint.
BioImagene's products for the pathology market are Pathiam, iScanT, a research application, and 3i Technology, their Integrated Image Informatics technology. In addition to their clinical pathology applications and research applications, BioImagene has a Scientific Image Management System (SIMST) designed for pharmaceutical companies.
Uttarwar believes digital pathology is an obvious next step in medicine. "It's a natural progression. You can see where other industries have adapted digital technology. Radiology has gone digital and films are gone and the companies that made those films have been replaced by the companies that handle the digital technology. Pathology is probably the only island in the hospital system that is left undigitized. The comfort, the convenience, the efficiency, the accuracy--all of these compute to making digital pathology a reality."
Psyche Systems Corporation
Psyche Systems (Milford, MA) is not a digital pathology company per se, but a laboratory information system. They offer a number of different solutions for information management in a variety of laboratory areas, including anatomic pathology. Their AP solution is called the WindoPath Anatomic Pathology Information System, which has a modular, customizable design and can be integrated into several different laboratory information systems.
James Gearheart, laboratory sales director for Psyche, says, "WindoPath is an application that will be open on the pathologist's desktop. Whatever types of software are being used affiliated with their microscope's camera, WindoPath will pull in and integrate with their report. They can put captions on the images and they can annotate the image and point out specific parts that will print with the image anywhere on the report."
Lisa Jean Clifford, Psyche's senior director of marketing and business development says, "One of the trends we are seeing is that pathology labs are looking to incorporate the images into the final results they can share with physicians and their physician's customers--as a requirement, not just for a report to look pretty. They want them as a true reference point. So one of the things they are looking for is high digital imaging quality."
To that end, Psyche has entered into a strategic relationship with Milestone Medical (Shelton, CT). Among Milestone's products are MacroPATH D and MacroVIEW, which are digital imaging systems designed less for microscope slides than for gross dissection imaging.
Interestingly, Psyche developed a product called the PocketPath Mobile Access that would allow pathology images and reports be downloaded directly to a physician's PDA or Palm Pilot. Gearheart notes that it was not a product that took off in the market and Psyche has discontinued marketing it. "There's never been a call for it in the marketplace."
Clifford says, "It's a nice concept and we do have the ability to bring that out of our cache of products, but there just wasn't any real demand for it. If you keep in mind the quantity of information on the final report in pathology, it's really hard to view that on a handheld device. There is a lot of scrolling that needs to take place or the images are small."
MIMvista Corporation
Based in Cleveland, Ohio, MIMvista recently made the news--somewhat contrary to Psyche's comments about PocketPath--because of their development of a pathology imaging system specifically for Apple's iPhone. MIM stands for Multi-modality Imaging, which has its roots in a digital radiology system dubbed Fusion.
MIMvista has a significant software presence in areas of radiology and nuclear medicine as well as the various "reading rooms" for neurology, cardiology, and radiation oncology. Jerimy Brockway, director of software architecture for MIMvista, says, "We originally wrote the Fusion software for Multi-modality Region Alignment and that served as the foundation for MIM, which is our desktop application--our flagship application. Since then we have developed powerful modules; for example, we do automated segmentation of images for treatment planning. We have formal registration where we can take an entire atlas of a prior subject and choose the subject that best matches today's patient." They are then able to compare the patient's digital images with a "model" patient's images.
In terms of the iPhone application, what MIMvista will do is bundle the imaging disk sets and send them to the iPhone application server. Brockway says, "We can call it in from the iPhone and call over whichever ones we want to see. So the physician can be offsite or maybe a referring doctor or they need to give some assistance to a particular read and they don't need to be tied to a workstation."
Although there's a definite gee-whiz quality to seeing pathology images on an iPhone, it's not clear--like Psyche's application--whether there will be a real demand for it. Although the imaging and screen quality of the iPhone is impressive and quite flexible, it's still a two-inch by three-inch screen. Brockway suspects this might be limited to the iPhone. "My impression is that other applications would be unlikely. The iPhone platform affords developers quite a bit of richness, as far as the platform goes. All plugs for Apple aside, it really makes it possible for the first time, in my opinion. I've been doing this for three or four years and my impression is it wouldn't be possible on any of the other current platforms."
Brockway notes that radiologists have a certain methodology they employ when working with images. "They move back and forth through images and it's as if they are constructing 3D images in their head from the experience they have. If it's not quick enough or there is inconsistency in the speed, it really disrupts their ability to make that picture in their head. Our current solution is very fluid, very fast, and we feel that once people are able to use the application, they're going to find it's something they can use on a day-to-day basis if they need to."
Another potential use for the iPhone application may be by patients. Brockway says, "Traditionally, what's done is patients will sit with their oncologist, for example, in a reading room. It's not very easy to get everything together and show patients their images. The application is going to be free on the Apple application store, so end-users can be physicians or patients. On the patient side they can do two things: They can have it just to have it and show people, but also to transfer. So many times users are given the CD and you need to take that CD somewhere or request a CD be made so you can take it to the referring doctor. But what this will allow is for patients to just receive the images, then transfer them from the iPhone to the referring doctor's workstation."
Omnyx
As mentioned earlier, in June 2008, GE Healthcare and the University of Pittsburgh Medical Center entered into a joint agreement to start a digital pathology device company called Omnyx. Omnyx will be headquartered in Pittsburgh and also have a site in Piscataway, NJ, in addition to facilities in Israel and in Albany, New York. As yet, Omnyx does not have an actual product, although they plan to have a prototype device developed by the end of 2008 and expect to launch a product in 2010. Gene Cartwright, CEO of Omnyx says, "We believe it will be a little less than two years before we have a product. I think that we'll be able to describe it in high level detail by the end of this year, but it's the sort of product that needs FDA approval and that adds a certain amount of time to it."
The joint project builds on UPMC's digital pathology developments and GE's technology, which includes advanced optics, image capture algorithms, and next-generation imaging platforms. Cartwright notes that the two big challenges for a clinical digital pathology system are handling the large numbers of slides produced daily and fitting all that digital information into a hospital's information system. "Those are two big challenges that none of the two, three, or four smaller digital pathology technology companies that exist today have really been able to take on. But GE has a lot of these capabilities today based on our radiology and cardiology products. So pathology ends up being more of a natural extension for a company like GE. We thought UPMC would be an excellent partner because they're expert in the field and they have a high level of interest--they need it for their own use."
Cartwright believes the reason the field of digital pathology is receiving so much interest at the moment is that some of the technical hurdles are close to being solved. "The main ones are speed of acquisition of an image, quality of the image, ability to navigate around the image without having to wait for the image to come up, and then the ability to stream images. The cost of storage has dropped by 30 to 40 percent a year."
GE apparently views this joint venture as a new way to innovate and marks a first-time relationship with an academic medical center. Cartwright says, "I have run joint ventures before between two more or less equal partners, and by equal I mean two partners that have the same sorts of background. In this case, you have a more corporate partner on the one hand, and there's not going to be more pull-and-tug because they understand their roles a lot better than a typical joint venture. In this, GE had to put up 50 percent of the money instead of 100 percent of the money, which means they can do twice as many things on their own. That's our goal, to do new and innovative things. If they work--and it's the intent in the contract--GE will buy out the UPMC part of the partnership."
Educational Use
John Woosley, MD, PhD, Professor of Pathology at the University of North Carolina at Chapel Hill, notes an increased use of digital slides in medical education. He sees it as an opportunity for medical schools to cooperate and share teaching materials, primarily because once a slide has been scanned, it costs nothing to duplicate
In Woosley's case, he utilizes the Aperio system. He has created a database of several thousand digital slides for teaching purposes. "I try to scan slides that are technically excellent and are very good illustrative examples of each pathologic process. Many of these slides are available to pathology residents from a departmental intranet for self-study."
Other slides are made available to medical students via the School of Medicine's server and are typically studied with referenced clinical findings and a synopsis of the pathologic features of each slide. Woosley says, "I can provide residents and medical students with a comprehensive collection of superb teaching slides that the department could not afford to provide in glass form."
Woosley notes that an even more important use of digital slides in education is their ready availability for use in illustrating lectures. "A great strength of virtual slides is that they do not become lost, broken, or faded as glass slides do. A specific virtual slide is much easier to find in an electronic database than its glass slide equivalent stored in a filing drawer."
He also notes that the images he acquires from an Aperio virtual slide using their ImageScope viewer are superior to any he could take at his own microscope using a digital camera. "The low magnification images that very effectively demonstrate many disease architectural patterns cannot be created at the microscope at all. In addition to lectures, images from virtual slides can be incorporated into a variety of interactive, self-instructional case exercises."
Conclusion
As noted, pathology is one of the last areas of clinical medicine to become digitized, following radiology and cardiac imaging. Typically the domain of microscope companies like Nikon, Zeiss and Olympus, a number of small companies have entered the market with new optics technology and digital information management software.
Although a number of companies and researchers have approached digital pathology over the last ten to fifteen years, they were hampered largely by the difficulty of acquiring high-resolution images of the entire microscope at high enough quality to be clinically useful. As digital image capture technology improved along with increased digital storage capacity at lower prices, digital pathology may have reached a tipping point where the technology is available at a reasonable cost.
Aside from microscope companies, the primary manufacturers of digital pathology solutions have tended to be small companies. However, as the recent joint venture between GE Healthcare and the University of Pittsburgh Medical Center suggests, large electronics companies may begin entering the market as it matures.
It's not clear how large that market may actually be. Omnyx's Cartwright says, "The assumption is the market will adopt digital pathology at the same rate that digital radiology was adopted. So in several years we believe--and at the price points we're assuming the market will support--that the market will be worth about $2 billion."
Aperio's Soenksen is more optimistic. "We've looked at the market and we've made a hypothetical full-adoption in the market and say it's close to $4 billion a year. That's about twice the size of what GE had in their analysis. We see more value in digital diagnosis that could be applied to automate things that pathologists are currently spending time on."
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