Skip Navigation LinksHome > May 2012 - Volume 19 - Issue 3 > Whole-slide Imaging: Routine Pathologic Diagnosis
Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e318253459e
Review Articles

Whole-slide Imaging: Routine Pathologic Diagnosis

Cornish, Toby C. MD, PhD*; Swapp, Ryan E. MD; Kaplan, Keith J. MD

Free Access
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Author Information

*Department of Pathology, Johns Hopkins University, Baltimore, MD

Division of Anatomic Pathology, Mayo Clinic, Rochester, MN

Carolinas Medical Center, Charlotte, NC

The authors have no funding or conflicts of interest to disclose.

Reprints: Keith J. Kaplan, MD, Carolinas Pathology Group, 1000 Blythe Blvd, 4th Floor, Charlotte, NC 28203 (e-mail: keithjkaplanmd@gmail.com).

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Abstract

Digital pathology systems offer pathologists an alternate, emerging mechanism to manage and interpret information. They offer increasingly fast and scalable hardware platforms for slide scanning and software that facilitates remote viewing, slide conferencing, archiving, and image analysis. Deployed initially and validated largely within the research and biopharmaceutical industries, WSI is increasingly being implemented for direct patient care. Improvements in image quality, scan times, and imageviewing browsers will hopefully allow pathologists to more seamlessly convert to digital pathology, much like our radiology colleagues have done before us. However, WSI creates both opportunities and challenges. Although niche applications of WSI technology for clinical, educational, and research purposes are clearly successful, it is evident that several areas still require attention and careful consideration before more widespread clinical adoption of WSI takes place. These include regulatory issues, development of standards of practice and validation guidelines, workflow modifications, as well as defining situations where WSI technology will really improve practice in a cost-effective way. Current progress on these and other issues, along with improving technology, will no doubt pave the way for increased adoption over the next decade, allowing the pathology community as a whole to harness the true potential of WSI for patient care. The digital decade will likely redefine how pathology is practiced and the role of the pathologist.

Whole-slide imaging (WSI), or “virtual” microscopy, involves the scanning (digitization) of glass slides to produce “digital slides.” WSI has been advocated for diagnostic, educational, and research purposes.1–5 When used for remote frozen section diagnosis, WSI requires a thorough implementation period coupled with a well-trained support personnel.6 Adoption of WSI for rendering pathologic diagnoses on a routine basis has been shown to be successful in only a few “niche” applications.7–10 Wider adoption will most likely require full integration with the laboratory information system, continuous automated scanning, high-bandwidth connectivity, massive storage capacity, and more intuitive user interfaces.4,11 Nevertheless, WSI has been reported to enhance specific pathology practices, such as scanning slides received in consultation or of legal cases, of slides to be used for patient care conferences, resident education,1 for quality assurance purposes,5,12,13 to retain records of slides to be sent out or destroyed by ancillary testing, and for performing digital image analysis.14,15 In addition to technical issues, regulatory and validation requirements related to WSI have yet to be adequately addressed.16 Although limited validation studies have been published using WSI,6,17,18 there are currently no standard guidelines for validating WSI for diagnostic use in the clinical laboratory. This review addresses the current status of WSI in pathology related to regulation and validation, the provision of remote and routine pathologic diagnoses, educational uses, implementation issues, and the cost-benefit analysis of adopting WSI in routine clinical practice.

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ADVANTAGES AND DISADVANTAGES

Although WSI is a relatively mature technology, a number of obstacles still impede its widespread adoption for primary diagnosis. These include both real and perceived disadvantages of WSI when compared with the traditional optical microscope (Table 1). Commonly cited disadvantages of WSI can be broadly characterized as (1) reduced quality; (2) impediments to workflow; (3) increased expense; and (4) threats to job security.

Table 1
Table 1
Image Tools
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Quality

Many pathologists remain concerned about the quality of the digital pathology experience. These concerns include both doubts about the overall quality of the images produced by the scanners as well as reservations about the digital slide viewer user experience.12 These concerns are not entirely unfounded. Although the quality of the digital pathology experience varies by both WSI system and the type of specimen being examined, several complaints about WSI are common to all platforms. A persistent concern about WSI is image quality, a concern that is occasionally echoed by studies of WSI.19 In traditional microscopy, image quality is entirely a function of the optics (primarily the objectives and eyepieces). In WSI, additional elements, including image resolution, compression quality, and focusing algorithms play key roles in the interpretation of a scanned slide. Image resolution, typically expressed in micrometers per pixel (mpp), is an important but frequently overlooked (and often misunderstood) aspect of WSI. Although the overall magnification in traditional microscopes can be understood as the product of the objective and eyepiece lenses, digital imaging replaces the human retina with a solid-state imaging sensor, usually a charged-coupled device chip. In WSI, image resolution is a composite function of the optical magnification in the scanner and the size and pixel density of the imaging sensor. Although WSIs are frequently referred to as “×20” or “×40” these are relative descriptors that refer only to the objective used in scanning. Typical resolutions for ×20 WSIs are around 0.5 mpp, however, at least 1 manufacturer is producing images at 0.275 mpp. The conventional wisdom is that “×20” WSIs are adequate for most diagnostic tasks, and several studies seem to confirm this notion.8 However, as “×40” scans quadruple both scan time and WSI file size, adoption of a “×20” standard has been driven as much by practicality as evidence. Poor focus can also contribute to poor image quality, as WSIs are typically acquired as a single plane (vs. z stacks) to minimize scan time and file size. Because a focus plane must be determined at scan time, WSIs seem to be far more sensitive to borderline or poor histologic preparation of slides and few WSIs are 100% in focus.

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Workflow

Comparisons are commonly drawn between “digital pathology” and “digital radiology.” When radiology “went digital,” a major incentive was the drastic streamlining of workflows that resulted from the elimination of film.20,21 Opinion of the impact on WSI on pathology workflow is mixed. In cases of geographic isolation with either stringent turnaround time (TAT) or few alternatives for efficiently transporting slides, WSI can improve workflow and the value added by this improvement may be sufficient to justify its implementation.8,22 In other applications, such as routine on-site sign-out, workflow may be negatively impacted by the use of WSIs. Scanning slides adds an additional, time-consuming step to the histology workflow. Although scan speeds continue to improve, the rate of improvement is slow. In a production environment, process overhead such as slide loading and unloading, quality control of scans, and rescanning of slides results in an average scan time considerably longer than that reported by manufacturers.23 Complete workflow digitization would be a significant undertaking. One group at a large academic hospital determined that adding a single current-generation scanner to the histology workflow would TAT by 10- to 20-fold. Minimizing the increase in TAT would require installing between 9 and 14 scanners.24 Some have proposed that the scanning effort required to implement a total “digital pathology” workflow would be more than offset by gains in workflow efficiency elsewhere, however, the existing evidence for these gains is lacking widespread validation by community standards at this time.

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Expense

High-speed, high-capacity slide scanners are expensive, costing between $100,000 to $250,000 for a single scanner and its associated software licenses. Maintenance and support contracts for this hardware and software are similarly expensive, costing tens of thousands of dollars per scanner annually. In addition to these direct costs, there are considerable indirect costs, including technician salaries and network and data storage costs. Extrapolating from their current scan rate (3% of their clinical histology laboratory’s total output), 1 large academic institution estimated an initial hardware and software cost of $2 million, $650,000 annually for support personnel, and $10,000 annually in storage costs for a complete digital conversion.23 Obviously, more modest applications with smaller scanning volumes do not require expenditures of this magnitude. However, disadvantages do exist at both ends of the volume spectrum: most scanners on the market are overkill for practices with small scanning volumes, whereas large laboratories would find they might need a dozen or more current-generation scanners to digitize their entire slide volume.24 A new generation of value-conscious slide scanners is emerging and may address some of these economic issues, but it remains to be seen whether they can provide the image quality, speed, and reliability necessary for clinical applications.

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Job Security

A lurking fear among some pathologists is that widespread adoption of telepathology could turn pathology services into a geographically unbounded commodity.25 Although the doomsday scenario of cheaply outsourcing pathology services to other countries seems very far fetched due to licensing restrictions, the deployment of telepathology services across state borders is already a reality.22,26,27 More concerning than the potential for offshoring is the very real possibility that telepathology could facilitate further consolidation of pathology services in large laboratories. This consolidation could lead to further market contraction, which could negatively affect pathologist salaries.

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REGULATORY AND MEDICOLEGAL ISSUES

Medicolegal, regulatory, and reimbursement issues for telepathology, as well as licensing, credentialing, and malpractice coverage, are becoming increasingly important. Because telepathology is still an evolving area of telemedicine, the legal and regulatory environment involving such practices is also evolving.16,27,28 Nevertheless, guidelines for primary opinion telepathology should always be driven from best practices in conventional laboratory procedures.

Telepathology may involve the transmission of digital images across state lines. This becomes problematic given that the definition of telemedicine and its laws vary greatly throughout the United States.

For example, some statutes and regulations refer to telemedicine as “interstate practice of medicine,” “remote medicine,” or “practicing medicine by electronic means.” Many states with large rural populations have developed complex telemedicine laws, whereas densely populated states do not refer to telemedicine at all in their statutes or regulations. Even for states that do not address telemedicine, it is generally assumed that any act of diagnosis or treatment recommendation such as telepathology is the practice of medicine in the state in which the patient is located. In the United States, it would thus be against public policy if the practice of medicine was considered to be in the location of the physician.29 In contrast, European scholars suggested that the law should recognize that the practice of telepathology be assigned to the site of the practitioner, not the patient.30 The assumption of these laws and regulations that specifically address telemedicine should be that the physician be physically located in the jurisdiction in which he/she has an unrestricted license and the patient is in a different jurisdiction.

Under the antikickback statute, it is a criminal offense to knowingly and willfully offer, pay, solicit, or receive any remuneration to induce referrals of items or services reimbursable by any federal health care program.

If an arrangement that would otherwise implicate the statute meets the requirements of all safe harbors, then the arrangement would not violate the statute. Although Medicare provides limited reimbursement for telemedicine services, this does not reduce the antikickback risks for telepathology arrangements, because such an arrangement could implicate the statute by inducing any other referrals beyond the telepathology services involved. For example, if the necessary intent was present, the antikickback statute would implicate an arrangement in which a hospital provided free telepathology equipment to a pathology group while the group’s outpatient biopsy specimens are processed at the hospital, assuming that the hospital collected a technical fee for each specimen and the pathology group could reassign the processing of the tissue to another facility.

With regard to medical malpractice and liability, there is little case law that currently addresses the unique liability issues that could arise in telemedicine. Applying traditional malpractice analysis to evaluate telepathology liability, specific questions that may arise relate to: (i) duty (eg, In which state is the patient located? In which state is the pathologist located?); (ii) breech of duty (eg, Is the pathologist properly trained to use the telemedicine equipment? Did the pathologist use the equipment properly?); (iii) damage caused by breech; and (iv) proximate cause (eg, Did the pathologist fail to use telepathology technology that could have prevented injury to the patient? What traditional pathology situations are similar to the telepathology act?). Finally, pathologists should make sure that their insurance will cover malpractice claims arising from telepathology diagnoses.

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VALIDATION OF DIGITAL PATHOLOGY FOR CLINICAL USE

The literature contains numerous studies comparing the diagnostic accuracy of reading digital histologic images slides to traditional microscopy. A review of the international literature by the College of American Pathologists (CAP) Work Group has suggested that during the last decade there were over 600 published studies related to clinical use of WSI.31 A careful examination of published studies reveals broad heterogeneity in this body of literature. In fact, very few of these published studies were designed to validate the use of WSI for rendering a primary diagnosis. Most of these publications describe the use of static imagery or robotic microscopy, primarily for telepathology.32–39 Although certain parallels can be drawn between the use of robotic and WSI systems, fundamental differences between these technologies make any of validation of one inapplicable to the other. Other studies primarily focused on the use of WSI in teaching,40,41 technical innovation,42 and quality assurance activities.43,44 Only around a dozen studies have compared WSI and glass slides for either routine histology or frozen section diagnosis (for a recent summary, see Jara-Lazaro and Thamboo9). In general, these studies have found high concordance between the diagnoses arrived at using WSI and glass slides. Few clinically significant discrepancies have been identified, and in studies that measured it, intraobserver agreement between WSI and glass slides was also generally very high. Despite these encouraging results, most of these studies were not optimally designed to validate WSI for general clinical use.

The most common problem in the existing validation literature is case selection. In most studies, only a narrow range of subspecialty specimens were examined. Such studies have focused on prostate/genitourinary,12,45,46 gastrointestinal,47 cutaneous,19,48,49 ovarian,17 thoracic/pulmonary,50 breast,42,44 renal,43 and neuropathology specimens.51 Studies that examine a wide selection of tissue types are few.6,37

Another problem with case selection is a tendency to select cases with either a known malignant diagnosis or that represent “consultation” or “challenging” material.45,46,52 In contrast to random or consecutive selection of cases, enrichment of a study for positive cases increases the pretest probability and artificially elevates the performance of the test. Although this may validate the use of WSI for a “consult” service, it does not address the question of routine primary diagnosis.

The last major problem with these studies is an occasional failure to assess intraobserver agreement when reading the same material using WSI and glass slides. Several studies instead only compare the WSI diagnosis to a “gold standard”—either a consensus diagnosis, expert diagnosis, sign-out diagnosis, or (in the case of frozen sections) the permanent section diagnosis.8,12,17,42 An optimal study comparing WSI and glass slides must account for variation in observer skill and threshold. In the case of digital mammography, this was demonstrated using a multiple-reader, multiple-case (MRMC) paradigm.53 Briefly, MRMC is a method for generating receiver operating characteristic curves for the comparison of imaging modalities.54 Key components of MRMC require (1) that a ground truth diagnosis is established for a given case; (2) that each reader reads all of his or her cases using both modalities (fully-crossed design) with an intervening washout period; (3) that each reader rates his or her confidence in the diagnosis; (4) that the sample of readers is representative of the population of readers at large; and (5) that the sample of cases is of adequate size and is representative of the population of cases at large.55 Although MRMC is well established in radiology, receiver operating characteristic curves are designed for binary decisions (cancer vs. no cancer) and it remains unclear how they might be applied in a general sense to histologic diagnoses. Regardless, the underlying concepts provide a model for designing high-quality validation studies of WSI. The CAP and others have made similar recommendations for designing validation methods.4,56 A recent study that adhered to many of these study design recommendations reported intraobserver agreement ranging from 71% to 84% and major intraobserver discrepancies of 3% to 7% when WSI was compared with glass.6

Despite the fragmented and somewhat flawed nature of individual studies, the sum of this evidence strongly suggests that WSI may be ready for clinical use. This notion is supported by the experiences of several groups already using it routinely.8,22,57 Given the current lack of Food and Drug Administration (FDA)-approved WSI systems, validation of specific WSI systems for well-defined purposes and patient populations is still necessary before use.

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PRIMARY H&E DIAGNOSIS USING DIGITAL PATHOLOGY

As with many technologies, societal, practice, regulatory, and reimbursement issues lag behind the early adopters but begin to catch-up with the technology offerings and eventually become the focus of attention. Official agencies, including the Clinical Laboratory Improvement Amendments (CLIA), the CAP, and the US FDA, have provided little guidance, and digital pathology vendors still have to learn what it means to provide instruments to a clinical laboratory. As digital pathology enters the clinical laboratory in a diagnostic capacity, it is crucial that physicians and laboratory professionals understand the regulatory requirements and how best to implement them.

The widespread confusion about the regulatory requirements for digital pathology originates from this question: What role does the US FDA play when it comes to the use of digital pathology in clinical laboratories? The answer, at the time this manuscript was being submitted for publication, is that these devices, or more importantly, these systems would be regarded as class III devices and therefore require premarket approval.

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Existing Guidelines

The Centers for Medicare and Medicaid Services regulate all clinical laboratory testing in the United States through CLIA (www.cms.gov/clia), established in 1988. Clinical laboratories need to meet CLIA standards to become licensed to operate.

No specific CLIA regulations exist for digital pathology yet in most cases digital pathology is just a different way of doing pathology. Therefore, the same regulatory requirements apply.

Here are the sections of the CLIA standard58 that must be carefully considered when implementing digital pathology in a clinical laboratory:

Section 493.1105: Retention Requirements.

Section 493.1251: Procedure Manual.

Section 493.1252: Test Systems, Equipment, Instruments, Reagents, Materials, and Supplies.

Section 493.1253: Establishment and Verification of Performance Specifications.

Section 493.1254: Maintenance and Function Checks.

Section 493.1255: Calibration and Calibration Verification Procedures.

Section 493.1256: Control Procedures.

Section 493.1291: Test Report.

The CAP provides a laboratory accreditation program that helps clinical laboratories to meet and exceed Centers for Medicare and Medicaid Services requirements as well as those of other national and state regulatory bodies. Laboratories must meet CAP’s accreditation checklists to gain accreditation.

The CAP is becoming increasingly engaged in digital pathology, but more catch-up and practical guidance is still required.

The American Telemedicine Association59 developed the first guidelines for Clinical Telepathology, but only in a working draft version. The CAP’s informatics committee then developed its recommendations for telepathology60 that went into CAP’s Laboratory General (GEN) checklist in 2007. These regulations are intended for the following applications: primary diagnosis made by telepathology, frozen section diagnoses, formal second-opinion consultations, and ancillary techniques in which the pathologist participates in the interpretation of images.

Here are the sections of the GEN checklist61 that need to be considered carefully when implementing digital pathology in a clinical laboratory:

Network Equipment (GEN 49000, 49500).

Telepathology (GEN 50057, 50614, 51171, 51728, 52285, 52842).

In 2010, CAP added a new digital image analysis section to the anatomic pathology (ANP) checklist with a focus on DNA analysis, morphometric analysis, and fluorescence in situ hybridization (FISH). For the first time, the retention of images is regulated but only for slides that are not readable throughout the duration of the 10-year retention period, such as FISH images. Also, the new American Society of Clinical Oncology/CAP guidelines for treatment critical markers seemed to quickly find their way into the ANP checklist (ANP 22969 to 23003) and thereby got clinical laboratories to implement the latest thoughts on new methods and methodologies.

Here are the sections of the ANP checklist62 that need to be considered carefully when implementing digital pathology in a clinical laboratory:

Procedure Manual (ANP 07328).

Quality Management (ANP 10050, 10200, 10250).

Surgical Pathology Reports (ANP 12500).

Fluorescence and Non-Fluorescence In-Situ Hybridization (FISH) (ANP 22965).

Digital Image Analysis (ANP 23004 to 23042) Instruments and Equipment.

Digital pathology systems are typically based on commercial, off-the-shelf components, such as pathology monitors and complex software systems.63

Digital pathology systems include slide scanners placed in clinical laboratories that perform a critical step of the testing process. As such, slide scanners are like any other instrument in the laboratory and require proper installation, calibration, and maintenance.

Clinical laboratories are required to provide well organized and documented archival, retrieval, and logistical procedures. Of special interest for digital pathology are, for example, the handling of original slides/blocks for consultation and legal procedures, routinely reviewing pertinent previous material with a surgical specimen, and sending and receiving secondary consultations. With digital pathology, pathology picture archive and communications systems (PACS) provide new archival, retrieval, and logistical capabilities for those procedures. The integration of pathology PACS into the clinical workflow needs to be carefully thought through. Pathology PACS must become part of the laboratory’s procedures.63

Glass slides must still be archived. With digital pathology, there are debates about whether the digital slide should be archived in addition to or instead of the glass slide. Today, there are no regulations in place concerning digital slides (with the exception of FISH), and the handling of digital slides is at the discretion of the clinical laboratory (ie, laboratories can delete the digital slides after use).

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The Current Status of FDA Clearance

The establishment and verification of performance specifications for new digital pathology applications is probably the most critical part that clinical laboratories struggle with today.

The validation of digital pathology applications is not that different from what clinical laboratories have already used to with traditional pathology; they are just not familiar with it yet. A good approach is to extrapolate from existing experience and apply the same regulatory requirements.

The CAP and the American Society of Clinical Oncology have started to release recommendation guidelines for treatment critical markers. Those guidelines are not specific for digital pathology; nevertheless they provide good insight in the latest thoughts on standardization and validation in clinical laboratories and could help when establishing new verification and validation procedures for digital pathology applications. In 2007, the first guideline was released for the poster child of biomarker human epidermal growth factor receptor 2 (HER2/neu).64 In 2010, a new guideline was released for estrogen receptor and progesterone receptor.65

The FDA has cleared several digital WSI systems for limited uses, such as the examination of immunohistochemistry (IHC) staining reactions. The FDA has not yet cleared or approved digital WSI for routine surgical pathology diagnosis to replace conventional light microscopy (interestingly, a class I device that never got FDA clearance).63

An overview by manufacturers in reverse chronological order of all existing FDA clearances for IHC applications, the oldest and most established field of digital pathology is presented in Table 2.

Table 2
Table 2
Image Tools

FDA clearances to date are provided for specific tissue types, stains, and reagents. IHC includes many different tissue types, stains, and reagent manufacturers. It would be virtually impossible for a manufacturer to obtain FDA clearances for all of those applications and then maintain them. The middle ground that seems to have emerged is that manufacturers provide FDA clearances only for breast tissue with HER2, estrogen receptor, and progesterone receptor. These then provide most clinical laboratories with enough confidence to use the systems off-label for other tissue types, stains, and reagents based on self-validation as a laboratory-developed test under CLIA regulations.

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The Future of Regulation and Validation

The FDA is now investigating how to best address digital pathology from a regulatory perspective. A meeting was held in October 2009 to seek the expert opinion of a public advisory panel on the replacement of H&E glass slides and conventional microscopy by WSI, specifically for purposes of making routine surgical pathology diagnosis.

A subsequent meeting was held at Pathology Visions 2011 (San Diego, CA). See http://digitalpathologyassociation.org/online-cme-at-pathology-visions

As of this writing, no formal guidance document has been placed in the public domain. A few topics of interest to readers that were discussed include:

* The CAP emphasized the importance of proper validation as even the slightest difference between WSI and conventional microscopy could have considerable public health implications.

* The evaluation of a WSI system should focus on the use of the tool in the context of how a diagnosis is rendered in the clinical practice. In particular, all slides from each case should be used for the evaluation rather than a representative slide.

* Given that there is a high diagnostic concordance among pathologists for many types of specimens and diagnoses, a large sample size is required to provide adequate statistical power.

* The challenge set and evaluation criteria should reflect the spectrum of diagnostic labels and secondary measures.

* The validation protocol should focus on how WSI systems affect intrapathologist variability, rather than the impact on the accuracy of the diagnosis.

* Approval of WSI systems should be specific for specimen type, not specific diagnoses.

* The CAP cautioned FDA that the approval for primary diagnosis for a specific specimen application may result in significant off-label use.

It seems that if FDA implemented all those suggestions, the burden for medical device manufacturers to obtain a clearance or approval of a digital pathology system for primary diagnosis would be extremely high.

Thus far the FDA has not released any guidance or provided a clear path on what digital pathology manufacturers will have to do to get FDA clearance or approval for a digital pathology system for primary diagnosis. It is safe to assume that the FDA will be able to provide more clarity and guidance, once the first digital pathology manufacturer seeking FDA clearance or approval has worked with the FDA through the process. But that might also mean that it could take some time.

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SUMMARY

Digital pathology is a new technology and industry that is entering clinical laboratories. Official agencies, including CLIA, CAP, and FDA, provide little guidance. Manufacturers still have to learn what it means to provide instruments into a clinical laboratory so they can help the clinical laboratories meet regulatory requirements.

At the end of the day, digital pathology is just a different way of doing pathology, and the same regulatory requirements apply. This article provided a regulatory overview and reference framework to help physicians and laboratory professionals with the implementation of digital pathology in their clinical laboratories. The regulatory requirements applying to digital pathology were identified, and the latest thoughts in the industry on the validation of digital pathology were discussed.

There is a gap between what manufacturers offer in terms of the digital pathology system, the hardware and software, and the proper implementation of a digital pathology solution in a clinical environment. Independent professional service groups with pathology, clinical laboratory, and digital pathology expertise that work with medical directors and laboratory managers can provide the guidance and assistance needed to fill this gap.

There is a gap between what manufacturers offer in terms of the digital pathology system, the hardware and software, and the proper implementation of a digital pathology solution in a clinical environment. Independent professional service groups with pathology, clinical laboratory, and digital pathology expertise that work with medical directors and laboratory managers can provide the guidance and assistance needed to fill this gap.

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Keywords:

whole-slide imaging; digital pathology; telepathology; clinical use; regulatory; legal; technical; professional; image; microscope; validation; routine diagnosis

© 2012 Lippincott Williams & Wilkins, Inc.

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