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. |
